Aryl substituted diketones

ABSTRACT

Aryl substituted diketones and keto-esters, useful as antiviral agents and insecticides, are prepared by reacting an arylalkyl or arylalkenyl iodide with a metal salt of the appropriate diketone or keto-ester.

This application is a continuation-in-part of copending application Ser. No. 436,611, filed Jan. 25, 1974, now U.S. Pat. No. 3,917,718 which in turn is a continuation-in-part of application Ser. No. 265,333, filed June 22, 1972, now U.S. Pat. No. 3,829,475.

This application relates to aryl substituted diketones and keto-esters, to the preparation thereof and to certain novel intermediates.

The compounds of the invention are of the structural formula ##STR1## wherein Y is selected from the group consisting of: ##STR2## R' is lower-alkanoyl of 2 to 6 carbon atoms; R" is lower-alkanoyl of 2 to 6 carbon atoms or carbo-lower-alkoxy of 2 to 6 carbon atoms;

R° is hydrogen, lower-alkyl of 1 to 4 carbon atoms or chloro;

R is hydrogen or lower-alkyl of 1 to 4 carbon atoms;

Z is a single bond, vinylene (only when the remainder of Y is unsaturated) or ethylene (only when Y is saturated);

Z' is a single bond, methylene or ethylene; and

Ar is phenyl, naphthyl or phenyl substituted by 3,4-methylenedioxy or from one to three monovalent substituents selected from the group consisting of lower-alkyl of 1 to 4 carbon atoms, lower-alkoxy of 1 to 4 carbon atoms, carbo-lower-alkoxy of 2 to 4 carbon atoms, halogen, nitro, trifluoromethyl, trifluoromethoxy, hydroxy, acyloxy of 1 to 10 carbon atoms, benzyloxy, alkanoylamino of 1 to 4 carbon atoms, dialkylamino where alkyl has from 1 to 4 carbon atoms, and aminosulfonyl.

The carbon chains of R, R', R", R° and Ar substituents can be straight or branched, although primary or secondary alkyl moieties are preferred.

When two or three monovalent substituents are present on the phenyl ring or Ar, they can be the same or different.

The compounds of the invention where Z and Z' are both single bonds and R° is hydrogen are prepared as described in the following Reaction Sequences A and B. ##STR3##

In the foregoing Reaction Sequence A, a 1-R-1-acetylcyclopropane of formula II, where R has the meaning given hereinabove, is treated with an aldehyde ArCHO in the presence of a base to give the arylvinyl 1-R-cyclopropyl ketone of formula III. The latter, when treated with an alkali metal aluminum hydride, preferably lithium aluminum hydride, is reduced at both the carbonyl group and the olefinic linkage to give an arylethyl 1-R-cyclopropyl carbinol of formula IV. This carbinol is then treated with phosphorus tribromide in the presence of a metal bromide such as lithium bromide to replace the hydroxy group by bromine, which product is then treated with zinc bromide to effect ring opening to form an arylalkenyl bromide of formula V. The latter with a metallic iodide is converted to the corresponding iodide of formula VI. The iodide then is treated with the alkali metal enolate salt of a diketone or keto-ester of formula (R')(R")CH-M⁺, where R' and R" have the meanings given hereinabove and M⁺ is an alkali metal, preferably lithium, sodium or potassium. the reaction takes place in an inert solvent under anhydrous conditions and produces a compound of formula I where R° is hydrogen and Y is --C(R)═CHCH₂ CH₂ --. Catalytic hydrogenation of the latter, for example with palladium, platinum or rhodium catalyst, reduces the olefinic linking to afford a compound of formula I where R° is hydrogen and Y is --CH(R)CH₂ CH₂ CH₂ --.

Alternatively, hydrogenation of the double bond may be performed earilier in the synthesis, upon the unsaturated bromide of formula V. Hydrogenation of the latter in the presence of palladium or platinum oxide catalyst produces a saturated bromide of formula ##STR4## The latter in turn is converted to the corresponding iodide; ##STR5## which then is treated with the metallo derivative (R') (R")CH-M+ to give I (R° is H; Y is --CH(R)CH₂ CH₂ CH₂).

It has also been found that saturated bromides of formula Va can be caused to react directly with the metallo derivative (R') (R")CH⁻ M⁺, without intermediate conversion to the iodides VIa, to form final products of formula I. The iodide reaction takes place at temperatures of 20°-60° C., whereas the bromide reaction requires a higher temperature, about 100°-150° C.

In the event that one or more nitro groups are present in the aromatic nucleus, double bond reductions are carried out by an alternative method in order to avoid reduction of the nitro group(s). This alternative method comprises treating the olefinic compounds with hydroxylamine and hydroxylamine O-sulfonic acid in sodium hydroxide solution [Durckheimer, Annalen 721, 240 (1969)[.

A further alternative approach to compounds within the scope of the present invention involves a Friedel-Crafts type reaction between an aromatic compound, ArH, and an omega-haloalkanoic acid halide. The carbonyl group of the resulting aromatic ketone is subsequently removed by reductive methods to give an aryl-aliphatic halide which is converted to the compounds of the invention by procedures already described. ##STR6##

In Reaction Sequence B the arylvinyl 1-R-cyclopropyl ketone of formula III is treated with an alkali metal borohydride, preferably sodium borohydride to reduce the carbonyl group but not the olefinic linkage and provide an arylvinyl 1-R-cyclopropyl carbinol of formula VII. By procedures analogous to those shown in Reaction Sequence A, the carbinol of formula VII is treated with phosphorus tribromide in the presence of a metal bromide and then with zinc bromide to give a diunsaturated aralkyl bromide of formula VIII. The latter is then converted to the corresponding iodide (IX), which reacts with the alkali metal enolate salt of a diketone or keto-ester to afford a compound of formula I where R° is hydrogen and Y is --C(R)═CHCH═CH--. If desired, the latter can be catalytically hydrogenated to produce a compound of formula I where Y is --CH(R)CH₂ CH₂ CH₂ --.

In the event that compounds of formula I where the variable Z defined above is vinylene (--CH═CH--) are desired, the same reaction sequence as in Z can be carried out starting with cinnamaldehyde or a substituted cinnamaldehyde of the formula OHC--CH═CH--Ar.

Also, the first step of Reaction Sequence A can be used to produce the corresponding aryl --CH═CH vinyl 1-R-cyclopropyl ketone for similar use as the starting material in Reaction Sequence B. Catalytic hydrogenation of the compounds where Z is vinylene affords the compounds where Z is ethylene.

If it is desired to obtain compounds of formula I wherein Ar is substituted by from one to three hydroxy groups, the reaction sequences can be carried out with the corresponding compounds where Ar is substituted by from one to three benzyloxy groups. The benzyloxy group or groups can then be cleaved by catalytic hydrogenolysis. Any unsaturated linkages in the aliphatic bridge are also hydrogenated at the same time. Alternatively, if it is desired to obtain compounds where Ar is substituted by one or more free hydroxy groups and where the aliphatic bridge is unsaturated, the hydroxy group(s) can be protected throughout the syntheses by esterification (as acetate or benzoate), and the ester hydrolyzed as the final step. The ester production method is of course also applicable to the preparation of compounds where the aliphatic bridge is saturated.

It is not, however, essential that phenolic hydroxy groups be protected in the form of esters or ethers at the final step of the synthesis because the diketone or keto ester reactant, R'CH₂ R" is more acidic than the phenolic hydroxyl; hence the desired alkylation with the iodides or bromides (VI, VIa, Va) will take place without affecting any phenolic hydroxy groups which may be present.

The compounds of formula I where the aryl group is substituted by acyloxy can also be prepared by conventional esterification of the corresponding hydroxy compounds of formula I with the appropriate acid, acid halide or acid anhydride. The acyloxy groups are derived from carboxylic acids having from one to about ten carbon atoms, and having a molecular weight less than about 200. Representative of the acyl radicals which can be present are lower-alkanoyl radicals, e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, capropyl, heptanoyl, octanoyl, trimethylacetyl, and the like; carboxy-lower-alkanoyl radicals, e.g., succinyl (β-carboxypropionyl); cycloalkyl-lower-alkanoyl radicals, e.g., β-cyclopentylpropionyl, β-cyclohexylpropionyl, and the like; monocarbocyclic aroyl radicals, e.g., benzoyl, p-toluyl, p-nitrobenzoyl, 3,4,5-trimethoxybenzoyl, and the like; monocarbocyclic aryl-lower-alkanoly or -alkenoyl radicals, such as phenylacetyl, β-phenylpropionyl, cinnamoyl, and the like; monocarbocyclic aryloxy-lower-alkanoyl radicals, such as p-chlorophenoxyacetyl, and the like; and amino-lower-alkanoyl, such as glycinyl, alaninyl, morpholinobutyrl, and the like. When monocarbocyclic aryl groups are present in the ester moieties, monocarbocyclic aryl includes phenyl and phenyl substituted by from one to three lower-alkyl, lower-alkoxy, halogen or nitro groups.

In the reaction of the arylalkyl iodides or arylalkenyl iodides of formulas VI or IX with the lithium enolate salt of a diketone or keto-ester, some of the iodide reactant undergoes dehydrohalogenation to produce a compound of the formula

    CH.sub.2 ═CH--Y--Ar

The byproducts of formula X are readily separated from the main products of formula I by chromatographic procedures, because the former are of more non-polar character than the latter. Selected compounds of formula X having the structure ##STR7## when R is lower-alkyl of 1-4 carbon atoms have been isolated and characterized and are within the purview of the invention. The dehydrohalogenation reaction occurs in the presence of any basic reagent.

The compounds of formula I when R° is chloro can be prepared by treating the corresponding compounds of formula I when R° is hydrogen with a chlorinating agent. An appropriate chlorinating agent is one which introduces a chlorine atom in a position alpha to a carbonyl group. Examples of appropriate chlorinating agents are t-butyl hypochlorite, cupric chloride and sulfuryl chloride.

The compounds of formula I where R° is lower-alkyl can be prepared by treating the corresponding compounds of formula I where R° is hydrogen with a lower-alkyl iodide in the presence of a strong base under anhydrous conditions. The strong base can be an alkali metal alkoxide, hydride or amide, or a strong organic amine such as 1,5-diazabicyclo[5.4.0]undec-5-ene.

The compounds of formula I above where Z' is CH₂ or CH₂ CH₂ are prepared by homologation reactions carried out on the intermediate iodides (formulas VI, VIa, IX). For one-carbon homologation (Z' is CH₂), the iodide is interacted with thioanisole and phenyllithium to produce a phenyl thioether where the iodine atom is replaced by C₆ H₅ SCH₂. The phenyl thioether is then heated with methyl iodide which replaces the C₆ H₅ S group by iodine, yielding the next higher homolog of the original iodide.

For two-carbon homologation (Z' is CH₂ CH₂), the intermediate iodide of formula VI, VIa or IX is condensed with an alkali metal salt of a malonic ester to give a compound of the formula ##STR8## The compound of formula XI is then hydrolyzed and decarboxylated with aqueous alkali to produce a mono-basic acid (XII):

    hooc--ch.sub.2 ch.sub.2 ch.sub.2 --y--ar                   XII

lithium-aluminum hydride reduction of the latter acid converts it to the alcohol (XIII):

    hoch.sub.2 ch.sub.2 ch.sub.2 ch.sub.2 --y--ar              XIII

the latter alcohol is converted to the corresponding iodide by treating its p-toluenesulfonate ester with sodium iodide. The iodide, when condensed with the alkali metal salt of a diketone or keto ester, (R') (R")CH-M+, affords compounds of formula I where Z' is CH₂ CH₂.

A further and preferred aspect of the invention resides in compounds of the formula ##STR9## wherein R' and R" are lower-alkanoyl of 2-6 carbon atoms and n is an integer from 4 to 8, inclusive. The compounds where n is 6-8 can be prepared by methods already described. The compounds where n is 4-5, as well as the compounds where n is 6-8, can be prepared by an alternative synthetic approach starting with anisole. Anisole is subjected to a Friedel-Crafts reaction with an acid halide of the formula X'(CH₂)_(n-1) COX' where X' is chlorine or bromine to give a halo-ketone of the formula X'(CH₂)_(n-1) COC₆ H₄ OCH₃ (-p). The latter is catalytically reduced to a haloalkyl substituted anisole, X'(CH₂)_(n) C₆ H₄ OCH₃ (-p), which is then converted to the iodide, I(CH₂)_(n) C₆ H₄ OCH₃ (-p) and demethylated to the phenol, I(CH₂)_(n) C₆ H₄ OH(-p). The latter with an alkali metal salt of a diketone R'CH₂ R" produces a compound of formula XIV. In the event X' in the compound X'(CH₂)_(n) C₆ H₄ OCH₃ (-p) is bromine the conversion to the iodide and the demethylation can occur simultaneously by using hydriodic acid.

Biological evaluation of the compounds of formula I and XIV has shown that they possess antiviral activity. They have been found to be effective against one or more of a large variety of RNA and DNA viruses, including Myxoviruses, e.g. influenza types A₀, A₁, A-2, B; Paramyxoviruses, e.g. para-influenza types 1, 2, 3, and mumps virus; Picornaviruses, e.g. human rhinoviruses, Coxsackie viruses types A, B, ECHO viruses, equine rhinoviruses; Reoviruses, types 1, 2, 3; Arboviruses, e.g. equine encephalomyelitis (Eastern, Western and Venezuelan), Semliki Forest virus; miscellaneous RNA viruses, e.g. measles, distemper, respiratory syncytial, rubella, vesicular stomatitis, hepatitis; Herpes viruses, e.g. HSV type I, II, herpesvirus simiae, herpesvirus varicellae, infectious bovine rhinotracheitis, cytomegalovirus, Marek's disease virus, Epstein-Barr virus; Poxviruses, e.g. variola, vaccinia; leukemogenic viruses. Both in vitro and in vivo antiviral activity have been found in the compounds of the invention. The in vitro testing of the compounds showed that they had minimal growth inhibitory concentrations (mic) ranging from about 0.3 to about 50 micrograms per milliliter. The mic values were determined by standard serial dilution procedures. Certain of the intermediates of formulas III, IV and VII also showed antiviral activity.

The compounds of formulas I and Xa have also been found to possess pesticidal activity. They showed juvenile hormone-like activity when tested under simulated field conditions in a greenhouse against one or more of the following pest species: yellow mealworm pupae, dock beetle larvae, cabbage looper larvae, yellow fever mosquito larvae and rhodnius prolixus nymph.

The structures of the compounds of the invention were established by the modes of synthesis, by elementary analysis, and by infrared and nuclear magnetic resonance spectral determinations.

A further aspect of the invention relates to compositions for combatting arthropods by hindering the maturation thereof which comprise an effective amount of at least one compound of formula I in admixture with a suitable carrier or diluent, and to the method of combatting arthropods at any stage of their development by contacting them with said compositions.

The compositions of the invention are effective against insects at any stage of their development short of the final adult form, i.e. at the egg, larval or pupal stages. The compounds can be formulated in conventional manner as solutions, emulsions, suspensions, dusts and aerosol sprays. The pesticide compositions of the invention can contain adjuvants found normally in such preparations, including water and/or organic solvents such as acetone, dimethylformamide, sesame oil, petroleum oils, and the like. Emulsifying and surface active agents may also be added. Dust formulations can contain talc, diatomaceous earth, kaolin, bentonite, calcium carbonate, wood, flour, cork, carbon, and the like. The aerosol sprays contain propellants such as dichlorodifluoromethane. The compounds of this invention can be employed as the sole pesticide component or they can be used in admixture with other compounds having similar utility. While the concentration of active ingredient can vary within rather wide limits, ordinarily the pesticide will comprise not more than about 10%, and preferably about 1% by weight of the composition.

A still further aspect of the invention relates to compositions for combatting viruses which comprise an antivirally effective amount of at least one compound of formula I in admixture with a suitable carrier or diluent, and to the method of combatting viruses by contacting the locus of said viruses with said compositions.

The antiviral compositions are formulated by preparing a dilute solution or suspension in an organic or aqueous-organic medium, for example ethyl alcohol, acetone, dimethylsulfoxide, and the like; and are applied to the locus to be disinfected by conventional means such as spraying, swabbing or immersing. Alternatively, the compounds can be formulated as ointments or creams by incorporating them in conventional ointment or cream bases, such as alkylpolyether alcohols, cetyl alcohol, stearyl alcohol and the like; as jellies by incorporating them in conventional jelly bases such as glycerin and tragacanth; or as aerosol sprays or foams.

The following examples will further illustrate the invention.

PREPARATION OF INTERMEDIATES A. 2-Arylvinyl cyclopropyl ketones (III)

A1. 2-(3,4-Methylenedioxyphenyl)vinyl 1-ethylcyclopropyl ketone [III; Ar is 3,4-methylenedioxyphenyl, R is C₂ H₅ ].

A mixture of 33.6 g. (0.3 mole) of 1-ethylcyclopropyl methyl ketone and 45 g. (0.3 mole) of piperonal in 21 ml. of ethanol was stirred at room temperature, and 21 ml. of 20% aqueous sodium hydroxide was added dropwise over a period of 30-45 minutes. The mixture was warmed at 40°-60° C. for three hours with stirring. The solution was then cooled to 0°-10° C., 0.2 ml. of glacial acetic acid added, and the mixture was extracted with ether. The ether extracts were concentrated, and the residue dissolved in 200 ml. of 95% ethanol, which solution when cooled caused separation of a solid product. The latter was recrystallized from 150 ml. of methanol to give 39 g. of 2-(3,4-methylenedioxyphenyl)vinyl 1-ethylcyclopropyl ketone, m.p. 62°-64° C.

A2. 2-(3,4-Methylenedioxyphenyl)vinyl cyclopropyl ketone [III; Ar is 3,4-methylenedioxyphenyl, R is H] was prepared from 8.4 g. of cyclopropyl methyl ketone and 15 g. of piperonal according to the procedure described above in Preparation A1, affording 21.5 g., m.p. 85°-87° C. when recrystallized from ethanol.

A3. 2-(3,4-Methylenedioxyphenyl)vinyl 1-methylcyclopropyl ketone [III; Ar is 3,4-methylenedioxyphenyl, R is CH₃ ] was prepared from 25.6 g. of 1-methylcyclopropyl methyl ketone and 39.3 g. of piperonal according to the procedure described above in Preparation A1, affording 29.5 g. of crystalline product.

A4. 2-(3,4-Dimethoxyphenyl)vinyl 1-ethylcyclopropyl ketone [III; Ar is 3,4-(CH₃ O)₂ C₆ H₃, R is C₂ H₅ ] was prepared from 22.4 g. of 1-ethylcyclopropyl methyl ketone and 33.2 g. of veratraldehyde according to the procedure described above in Preparation A1, affording 20.3 g., b.p. 156°-158° C. (0.02 mm.).

A5. 2-(4-Methoxyphenyl)vinyl cyclopropyl ketone [III; Ar is 4-CH₃ OC₆ H₄, R is H] was prepared from 84.1 g. of cyclopropyl methyl ketone and 136 g. of p-methoxybenzaldehyde according to the procedure described above in Preparation A1, affording 173.5 g., m.p. 70°-72° C. when recrystallized from ethanol.

A6. 2-Phenylvinyl cyclopropyl ketone [III; Ar is C₆ H₅, R is H] was prepared from 13.5 g,. of cyclopropyl methyl ketone and 17.1 g. of benzaldehyde according to the procedure described above in Preparation A1, affording 23.0 g., m.p. 58°-60° C. when recrystallized from absolute ethanol.

A7. 2-(4-Chlorophenyl)vinyl cyclopropyl ketone [III; Ar is 4-ClC₆ H₄, R is H] was prepared from 25.2 g. of cyclopropyl methyl ketone and 42 g. of p-chlorobenzaldehyde according to the procedure described above in Preparation A1, affording 31 g., m.p. 63°-65° C. when recrystallized from ethanol.

A8. 2-(p-Tolyl)vinyl cyclopropyl ketone [III; Ar is 4-CH₃ C₆ H₄, R is H] was prepared from 84.1 g. of cyclopropyl methyl ketone in 120 g. of p-tolualdehyde according to the procedure described above in Preparation A1, affording 158.7 g., colorless plates, m.p. 78°-80° C. when recrystallized from ethanol.

A9. 2-(4-Carboxyphenyl)vinyl 1-ethylcyclopropyl ketone [III; Ar is 4-HO₂ CC₆ H₄, R is C₂ H₅ ] was prepared from 67.2 g. of 1-ethylcyclopropyl methyl ketone and 90 g. of p-carboxybenzaldehyde according to the procedure described above in Preparation A1, affording 40 g., m.p. 183.5°-184.5° C. when recrystallized from acetonitrile and then repeatedly from isopropyl alcohol.

By following the procedure of Preparation A1 above, 1-isopropylcyclopropyl methyl ketone or 1-butylcyclopropyl methyl ketone can be caused to react with piperonal to give 2-(3,4-methylenedioxyphenyl)vinyl 1-isopropylcyclopropyl ketone [III; Ar is 3,4-methylenedioxyphenyl, R is (CH₃)₂ CH], or 2-(3,4-methylenedioxyphenyl)vinyl 1-butylcyclopropyl ketone [III: Ar is 3,4-methylenedioxyphenyl, R is CH₃ CH₂ CH₂ CH₂ ], respectively.

By following the procedure of Preparation A1 above, cyclopropyl methyl ketone can be caused to react with 3,4-dichlorobenzaldehyde, 2,4-dichlorobenzaldehyde, 4-bromobenzaldehyde, 4-fluorobenzaldehyde, 4-hydroxybenzaldehyde, 4-trifluoromethoxybenzaldehyde or 4-trifluoromethylbenzaldehyde to give, respectively, 2-(3,4-dichlorophenyl)vinyl cyclopropyl ketone [III; Ar is 3,4-Cl₂ C₆ H₃, R is H], 2-(2,4-dichlorophenyl)vinyl cyclopropyl ketone [III; Ar is 2,4-Cl₂ C₆ H₃, R is H], 2-(4-bromophenyl)vinyl cyclopropyl ketone [III; Ar is 4-BrC₆ H₄, R is H], 2-(4-fluorophenyl)vinyl cyclopropyl ketone [III; Ar is 4-FC₆ H₄, R is H], 2-(4-hydroxyphenyl)vinyl cyclopropyl ketone [III; Ar is 4-HOC₆ H₄, R is H], 2-(4-trifluoromethoxyphenyl)vinyl cyclopropyl ketone [III; Ar is 4-F₃ COC₆ H₄, R_(is) H], or 2-(4-trifluoromethylphenyl)vinyl cyclopropyl ketone [III; Ar is 4-F₃ CC.sub. 6 H₄, R is H]. 2-(4-Hydroxyphenyl)vinyl cyclopropyl ketone can be esterified with benzoyl chloride to give 2-(4-benzoyloxyphenyl)vinyl cyclopropyl ketone [III; Ar is 4-C₆ H₅ COOC₆ H₄, R is H].

According to the procedures of Preparations A1-A9 using the appropriate starting materials, the following compounds were prepared:

A10 . 2-(2,4-Dichlorophenyl)vinyl cyclopropyl ketone [III; Ar is 2,4-Cl₂ C₆ H₃, R is H], yellow solid m.p. 85°-87° C. (from isopropyl alcohol).

A11. 2-(4-Acetamidophenyl)vinyl cyclopropyl ketone [III; Ar is 4-CH₃ CONHC₆ H₄, R is H], yellow crystals, m.p. 191°-192° C.

A12. 1-Cyclopropy-5-(p-methoxyphenyl)-2,4-pentadien-1-one, C₃ H₅ COCH═CHCH═-CH--C₆ H₄ OCH₃ -4, yellow solid, m.p. 131°-132.5° C. (from ethanol) prepared from 4-methoxycinnamaldehyde and cyclopropyl methyl ketone.

A13. 2-(4-Dimethylaminophenyl)vinyl cyclopropyl ketone [III; Ar is 4-(CH₃)₂ NC₆ H₄, R is H], yellow solid, m.p. 137°-139° C. (from ethanol,) active against equine rhino virus in vitro at 12 micrograms per milliliter.

A14. 2-(4-Benzyloxyphenyl)vinyl cyclopropyl ketone [III; Ar is 4-C₆ H₅ CH₂ OC₆ H₄, R is H], cream-colored solid, m.p. 111°-113° C. (from ethanol), active against equine rhino virus in vitro at 12 micrograms per milliter.

A15. 2-(3,4-Dibenzyloxyphenyl)vinyl cyclopropyl ketone [III; Ar is 3,4-(C₆ H₅ CH₂ O)₂ C₆ H₃, R is H], cream-colored solid, m.p. 100°-102° C. (from methanol), active against equine rhino virus in vitro at 1.5 micrograms per milliliter.

A16. 2-(4-Trifluoromethoxyphenyl)vinyl cyclopropyl ketone [III; Ar is 4-F₃ COC₆ H₄, R is H].

A17. 2-(1Naphthyl)vinyl cyclopropyl ketone [III; Ar is 1-naphthyl, R is H].

A18. 2-(4-Fluorophenyl)vinyl cyclopropyl ketone [III; Ar is 4-FC₆ H₄, R is H].

A19. 2-(4-Diethylaminophenyl)vinyl cyclopropyl ketone [III; Ar is 4-(C₂ H₅)₂ NC₆ H₄, R is H], yellow solid, m.p. 79°-81° C. (from ethanol).

A20. 2-(4-Benzyloxy-3,5-dimethoxyphenyl)vinyl cyclopropyl ketone [III; Ar is 3,5-(CH₃ O)₂ -4-C₆ H₅ CH₂ OC₆ H₂, R is H], light yellow crystals, m.p. 98°-99° C. (from ethanol).

A21. 2-(3-Iodo-4-methoxyphenyl)vinyl cyclopropyl ketone [III; Ar is 3-I-4-CH₃ OC₆ H₃, R is H], light yellow solid, m.p. 89°-90° C., active against equine rhino virus in vitro at 6 micrograms per milliliter.

B. 2-Arylethyl cyclopropyl carbinols (IV) and 2-arylvinyl cyclopropyl carbinols (VII)

B1. 2-(3,4-Methylenedioxphenyl)ethyl 1-ethylcyclopropyl carbinol [IV; Ar is 3,4-methylenedioxophenyl, R is C₂ H₅ ].

A suspension of 15 g. of lithium aluminum hydride in about 500 ml. of tetrahydrofuran was heated at reflux while a solution of 60 g. of 2-(3,4-methylenedioxyphenyl)vinyl 1-ethylcyclopropyl ketone (Preparation A1) in 150 ml. of tetrahydrofuran was added dropwise over a period of 2-3 hours. The reaction mixture was heated at reflux for two hours, cooled, and then water was added very cautiously. Excess anhydrous sodium sulfate was added, the mixture filtered, and the filter cake washed several times with chloroform. The combined filtrate and washings were evaporated to dryness to give 53 g. of an oil consisting of 2-(3,4-methylenedioxyphenyl)ethyl 1-ethylcyclopropyl carbinol.

B2. 2-(3,4-Methylenedioxyphenyl)ethyl cyclopropyl carbinol [IV; Ar is 3,4-methylenedioxyphenyl, R is H] was prepared from 18.4 g. of 2-(3,4-methylenedioxyphenyl)vinyl cyclopropyl ketone (Preparation A2) and 3.1 g. of lithium aluminum hydride according to the procedure described above in Preparation B1, affording 11.5 g., b.p. 116°-122° C. (0.005 mm.), m.p. 64°-65° C. when recrystallized from ether.

B3. 2-(3,4-Methylenedioxyphenyl)ethyl 1-methycyclopropyl carbinol [IV; Ar is 3,4-methylenedioxyphenyl, R is CH₃ ] was prepared from 23.4 g. of 2-(3,4-methylenedioxyphenyl)vinyl 1-methylcyclopropyl ketone (Preparation A3) and 3.88 g. of lithium aluminum hydride according to the procedure described above in Preparation B1, affording 18.8 g., b.p. 120°-130° C. (0.003 mm.).

B4. 2-(3,4-Dimethoxyphenyl)ethyl 1-ethylcyclopropyl carbinol [IV; Ar is 3,4-(CH₃ O)₂ C₆ H₃, R is C₂ H₅ ] was prepared from 15 g. of 2-(3,4-dimethoxyphenyl)vinyl 1-ethylcyclopropyl ketone (Preparation A4) and 2.2 g. of lithium aluminum hydride according to the procedure described above in Preparation B1, affording 10 g., b.p. 148°-150° C. (0.01 mm.).

B5. 2-(4-Methoxyphenyl)ethyl cyclopropyl carbinol [IV; Ar is 4-CH₃ OC₆ H₄, R is H] was prepared from 50 g. of 2-(4-methoxyphenyl)vinyl cyclopropyl ketone (Preparation A5) and 9.7 g. of lithium aluminum hydride according to the procedure described above in Preparation B1, affording 42 g., b.p. 116°-117° C. (0.05 mm.).

B6.2-Phenylethyl cyclopropyl carbinol [IV: Ar is C₆ H₅, R is H] was prepared from 23 g. of 2-phenylvinyl cyclopropyl ketone (Preparation A6) and 5.22 g. of lithium aluminum hydride according to the procedure described above in Preparation B1, affording 18.5 g., b.p. 89°-90° C. (0.02 mm.).

B7. 2-(4-Chlorophenyl)ethyl cyclopropyl carbinol [IV; Ar is 4-ClC₆ H₄, R is H] was prepared from 31 g. of 2-(4-chlorophenyl)vinyl cyclopropyl ketone (Preparation A7) and 5.87 g. of lithium aluminum hydride according to the procedure described above in Preparation B1, affording 23.8 g., b.p. 105°-106° C. (0.1 mm.).

B8. 2-(p-Tolyl)ethyl cyclopropyl carbinol [IV; Ar is 4-CH₃ C₆ H₄, R is H] was prepared from 158 g. of 2-(p-tolyl)vinyl cyclopropyl ketone (Preparation A8) and 33.2 g. of lithium aluminum hydride according to the procedure described above in Preparation B1, affording 137 g., b.p. 97°-98° C. (0.13 mm.).

B9. 2-(4-Carboxyphenyl)vinyl 1-ethylcyclopropyl carbinol [VII; Ar is 4-HO₂ CC₆ H₄, R is C₂ H₅ ].

To a stirred suspension of 34.0 of 2-(4-carboxyphenyl)vinyl 1-ethylcyclopropyl ketone (Preparation A9) in 500 ml. of ice water was slowly added 11 g. of sodium borohydride over a one hour period. The mixture was stirred for about sixteen hours and then cautiously acidified with ice-cold concentrated hydrochloric acid. The solid material was collected by filtration and dissolved in ether. The ether solution was dried over anhydrous magnesium sulfate and concentrated to give 33.2 g. of 2-(4-carboxyphenyl)vinyl 1-ethycyclopropyl carbinol, m.p. 130°-131° C. when recrystallized from toluene.

B10. 2-(4-Carboxyphenyl)ethyl 1-ethylcyclopropyl carbinol [IV: Ar is 4-HO₂ CC₆ H₄, R is C₂ H₅ ].

A solution of 29 g. of 2-(4-carboxyphenyl)vinyl 1-ethylcyclopropyl carbinol (Preparation B9) in 200 ml. of ethanol was hydrogenated in the presence of 1 g. of palladium-on-carbon catalyst. There was thus obtained 28 g. of 2-(4-carboxyphenyl)ethyl 1-ethylcyclopropyl carbinol, colorless crystals, m.p. 116°-117.5° C.

B11. 2-(3,4-Methylenedioxyphenyl)vinyl 1-ethylcyclopropyl carbinol [VII; Ar is 3,4-methylenedioxyphenyl, R is C₂ H₅ ].

To a cold solution of 5 g. of 2-(3,4-methylenedioxyphenyl)vinyl 1-ethylcyclopropyl ketone (Preparation A1) in 50 ml. of methanol was added in portions 1.56 g. of sodium borohydride. The mixture was stirred at room temperature for two hours, then diluted with water and extracted with ether. The ether extracts were dried and concentrated to give 3.6 g. of 2-(3,4-methylenedioxyphenyl)vinyl 1-ethylcyclopropyl carbinol as a colorless oil.

By replacing the 2-(3,4-methylenedioxyphenyl)vinyl 1-ethylcyclopropyl ketone in Preparation B1 above by a molar equivalent amount of 2-(3,4-methylenedioxyphenyl)vinyl 1-isopropylcyclopropyl ketone, 2-(3,4-methylenedioxyphenyl)vinyl 1-butylcyclopropyl ketone, 2-(3,4-dichlorophenyl)vinyl cyclopropyl ketone, 2-(2,4-dichlorophenyl)vinyl cyclopropyl ketone, 2-(4-bromophenyl)vinyl cyclopropyl ketone, 2-(4-fluorophenyl)vinyl cyclopropyl ketone, 2-(4-benzoyloxyphenyl)vinyl cyclopropyl ketone, 2-(4-trifluoromethoxyphenyl)vinyl cyclopropyl ketone or 2-(4-trifluoromethylphenyl)vinyl cyclopropyl ketone there can be obtained, respectively, 2-(3,4-methylenedioxyphenyl)ethyl 1-isopropylcyclopropyl carbinol [IV; Ar is 3,4-methylenedioxyphenyl, R is (CH₃)₂ CH], 2-(3,4-methylenedioxyphenyl)ethyl 1-butylcyclopropyl carbinol [IV; Ar is 3,4-methylenedioxyphenyl, R is CH₃ CH₂ CH₂ CH₂ ], 2-(3,4-dichlorophenyl)ethyl cyclopropyl carbinol [IV; Ar is 3,4-Cl₂ C₆ H₃, R is H], 2-(2,4-dichlorophenyl)ethyl cyclopropyl carbinol [IV; Ar is 2,4-Cl₂ C₆ H₃, R is H], 2-(4-bromophenyl)ethyl cyclopropyl carbinol [IV; Ar is 4-BrC₆ H₄, R is H], 2-(4-fluorophenyl)ethyl cyclopropyl carbinol [IV; Ar is 4-FC₆ H₄, R is H], 2-(4-benzoyloxyphenyl)ethyl cyclopropyl carbinol [IV; Ar is 4-C₆ H₅ COOC₆ H₄, R is H], 2-(4-trifluoromethoxyphenyl)ethyl cyclopropyl carbinol [IV; Ar is 4-F₃ COC₆ H₄, R is H], or 2-(4-trifluoromethylphenyl)ethyl cyclopropyl carbinol [IV; Ar is 4-F₃ CC₆ H₄, R is H].

According to the procedures of Preparation B1-B11 using the appropriate starting materials, the following compounds were prepared:

B12. 2-(2,4-Dichlorophenyl)ethyl cyclopropyl carbinol [IV; Ar is 2,4-Cl₂ C₆ H₃, R is H], b.p. 119°-126° C. (0.2 mm.), prepared from compound of Preparation A10.

B13. 2-(4-Acetamidophenyl)ethyl cyclopropyl carbinol [IV; Ar is 4-CH₃ CONHC₆ H₄, R is H], m.p. 142°-143° C., prepared from compound of Preparation A11.

B14. 4-(4-Methoxyphenyl)-3-butenyl cyclopropyl carbinol, C₃ H₅ CH(OH)CH₂ CH₂ CH═CHC₆ H₄ OCH₃ -4, b.p. 131°-132° C. (0.1 mm.), prepared from compound of Preparation A12.

B15. 2-(4-Dimethylaminophenyl)vinyl cyclopropyl carbinol [VII; Ar is 4-(CH₃)₂ NC₆ H₄, R is H], cream-colored solid, m.p. 76°-78° C. (from ethanol-pentane), prepared from compound of Preparation A13.

B16. 2-(4-Dimethylaminophenyl)ethyl cyclopropyl carbinol [IV; Ar is 4-(CH₃)₂ NC₆ H₄, R is H], pale yellow oil, b.p. 126°-128° C. (0.2 mm.), prepared from compound of Preparation A13, active against equine rhino virus in vitro at 12 micrograms per milliliter.

B17. 2-(4-Benzyloxyphenyl)ethyl cyclopropyl carbinol [IV; Ar is 4-C₆ H₅ CH₂ OC₆ H₄, R is H], m.p. 76°-77° C. (from ether-pentane), prepared from compound of Preparation A14.

B18. 2-(3,4-Dibenzyloxyphenyl)ethyl cyclopropyl carbinol [IV; Ar is 3,4-(C₆ H₅ CH₂ O)₂ C₆ H₃, R is H], m.p. 62°-64° C. (from etherpentane), prepared from compound of Preparation A15, active against equine rhino virus in vitro at 6 micrograms per milliliter.

B19. 2-(4-Trifluoromethoxyphenyl)ethyl cyclopropyl carbinol [IV; Ar is 4-F₃ COC₆ H₄, R is H], prepared from compound of Preparation A16.

B20. 2-(1-Naphthyl)ethyl cyclopropyl carbinol [IV; Ar is 1-naphthyl, R is H], b.p. 145°-146° C. (0.01 mm.), prepared from compound of Preparation A17.

B21. 2-(4-Fluorophenyl)ethyl cyclopropyl carbinol [IV; Ar is 4-FC₆ H₄, R is H], b.p. 90°-93° C. (0.2 mm.), prepared from compound of Preparation A18.

B22. 2-(4-Diethylaminophenyl)ethyl cyclopropyl carbinol [IV; Ar is 4-(C₂ H₅)₂ NC₆ H₄, R is H], pale yellow oil, b.p. 129°-131° C. (0.15 mm.), prepared from compound of Preparation A19.

B23. 2-(4-Benzyloxy-3,5-dimethoxyphenyl)ethyl cyclopropyl carbinol [IV; Ar is 3,5-(CH₃ O)₂ -4-C₆ H₅ CH₂ OC₆ H₂, R is H], prepared from compound of Preparation A20.

C. Arylalkenyl bromides (V, VIII) and arylalkyl bromides (Va)

C1. 3-Ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl bromide [V; Ar is 3,4-methylenedioxyphenyl, R is C₂ H₅ ].

To a solution of 26.4 g. (0.106 mole) of 2-(3,4-methylenedioxyphenyl)ethyl 1-ethylcyclopropyl carbinol in 250 ml. of ether, cooled to -30° C. under nitrogen, was added 18 ml. of collidine. Lithium bromide (26 g., 0.3 mole) was then added, the mixture cooled to -50° C. and 25 g. (0.09 mole) of phosphorus tribromide was added dropwise. The reaction mixture was stirred at -50° C. for ten minutes, allowed to warm to 0° C. over a three hour period and stirred at 0° C. for three hours. Collidine (30 ml.) was added, followed by 10 ml. of water. The reaction mixture was partitioned between water and ether, the ether layer washed with water and sodium chloride solution, and dried over anhydrous magnesium sulfate. The ether solution was concentrated to give an oily product used directly in the following reaction.

The latter product was dissolved in about 200 ml. of anhydrous ether and added in a fine stream to a stirred mixture of 27 g. of zinc bromide in 200 ml. of ether held at -30 to -35° C. The mixture was stirred, then allowed to warm to 0° C. during two hours, held there for thirty minutes, and then allowed to warm to room temperature over a three hour period and stirred for two hours longer. The reaction mixture was partitioned between ether and aqueous sodium chloride. The ether layer was washed three times with 500 ml. of water, then with sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to remove the solvent. The residue was redissolved in ether, washed with dilute aqueous sodium bicarbonate and with sodium chloride solution, and evaporated to give 23 g. of 3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl bromide as a straw-colored oil.

C2. 6-(3,4-Methylenedioxyphenyl)-3-hexenyl bromide [V; Ar is 3,4-methylenedioxyphenyl, R is H] was prepared from 11.5 g. of 2-(3,4-methylenedioxyphenyl)ethyl cyclopropyl carbinol (Preparation B2), 12 g. of phosphorus tribromide, 10 g. of lithium bromide and 12.7 g. of zinc bromide according to the procedure given above in Preparation C1, affording 12.5 g. of product as an oil.

C3. 3-Methyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl bromide [V; Ar is 3,4-methylenedioxyphenyl, R is CH₃ ] was prepared from 17.6 g. of 2-(3,4-methylenedioxyphenyl)ethyl 1-methylcyclopropyl carbinol (Preparation B3), 20.3 g. of phosphorus tribromide, 18.5 g. of lithium bromide and 21 g. of zinc bromide according to the procedure given above in Preparation C1, affording 19 g. of product as an oil.

C4. 3-Ethyl-6-(3,4-dimethoxyphenyl)-3-hexenyl bromide [V; Ar is 3,4-(CH₃ O)₂ C₆ H₃, R is C₂ H₅ ] was prepared from 16 g. of 2-(3,4-dimethoxyphenyl)ethyl 1-ethylcyclopropyl carbinol (Preparation B4), 16.8 g. of phosphorus tribromide, 16.8 g. of lithium bromide and 17.6 g. of zinc bromide according to the procedure given above in Preparation C1. The product was used directly in the succeeding step (Preparation D4) without isolation.

C5. 6-(4-Methoxyphenyl)-3-hexenyl bromide [V; Ar is 4-CH₃ OC₆ H₄, R is H] was prepared from 38.2 g. of 2-(4-methoxyphenyl)ethyl cyclopropyl carbinol (Preparation B5), 42.5 g of phosphorus tribromide, 35 g. of lithium bromide and 40 g. of zinc bromide according to the procedure given above in Preparation C1, affording 48 g of product as an oil.

C6. 6-Phenyl-3-hexenyl bromide [V; Ar is C₆ H₅, R is H] was prepared from 16.5 g. of 2-phenylethyl cyclopropyl carbinol (Preparation B6), 21.5 g. of phosphorus tribromide, 17.65 g. of lithium bromide and 20.7 g. of zinc bromide according to the procedure given above in Preparation C1, affording 21 g. of product as a pale yellow oil.

C7. 6-(4-Chlorophenyl)-3-hexenyl bromide [V; Ar is 4-ClC₆ H₄, R is H] was prepared from 21 g. of 2-(4-chlorophenyl)ethyl cyclopropyl carbinol (Preparation B7), 23 g. of phosphorus tribromide, 18.85 g. of lithium bromide and 22.5 g. of zinc bromide according to the procedure given above in Preparation C1, affording 25.5 g. of product as an oil.

C8. 6-(p-Tolyl)-3-hexenyl bromide [V; Ar is 4-CH₃ C₆ H₄, R is H] was prepared from 2-(p-tolyl)ethyl cyclopropyl carbinol (Preparation B8), phosphorus tribromide, lithium bromide and zinc bromide according to the procedure given above in Preparation C1.

C9. 3-Ethyl-6-(4-carbomethoxyphenyl)-3-hexenyl bromide [V; Ar is 4-CH₃ O₂ CC₆ H₄, R is C₂ H₅ ].

A mixture of 21.3 g. of 2-(4-carboxyphenyl)vinyl 1-ethylcyclopropyl carbinol (Preparation B9) and 500 ml. of methanol saturated with hydrogen chloride at 0° C. was stirred for one hour at 0° C. and then allowed to come to room temperature with stirring until the solution was complete. The reaction mixture was concentrated to dryness, the residue taken up in chloroform and washed with water and sodium bicarbonate solution, dried oer anhydrous magnesium sulfate and concentrated to give 24.4 g. of a light yellow oil. The latter product was dissolved in a small quantity of ether and added to a solution of 700 g. of znc bromide in 4 liters of anhydrous ether. The reaction mixture was stirred for twenty hours, then washed with water, dried over anhydrous magnesium sulfate and the solvent evaporated, affording 17.5 g. of 3-ethyl-6-(4-carbomethoxyphenyl)-3-hexenyl bromide as a light yellow oil.

C10. 3-Ethyl-6-(3,4-methylenedioxyphenyl)-3,5-hexadienyl bromide [VIII; Ar is 3,4-methylenedioxyphenyl, R is C₂ H₅ ] was prepared from 3.6 g. of 2-(3,4-methylenedioxyphenyl)vinyl 1-ethylcyclopropyl carbinol (Preparation B11), 3.5 g. of phosphorus tribromide, 4.5 g. of lithium bromide and 3.5 g. of zinc bromide according to the procedure given above in Preparation C1, affording 2 g. of product as an oil.

C11. 6-(4-Methoxyphenyl)hexyl bromide [Va; Ar is 4-CH₃ OC₆ H₄, R is H].

A mixture of 18.6 g. of 6-(4-methoxyphenyl)-3-hexenyl bromide (Preparation C5) and 0.21 g. of platinum oxide catalyst in 200 ml. of isopropyl alcohol was hydrogenated until 1 mole equivalent of hydrogen had been absorbed. The product was isolated and distilled to give 12.8 g. of 6-(4-methoxyphenyl)-hexyl bromide, b.p. 126°-128° C. (0.04 mm.).

C12. 6-Phenylhexyl bromide [Va; Ar is C₆ H₅, R is H] was prepared by hydrogenation of 21 g. of 6-phenyl-3-hexenyl bromide (Preparation C6) according to the procedure described above in Preparation C11, affording 16 g., b.p. 86°-87° C. (0.02 mm.).

C13. 6-(4-Chlorophenyl)hexyl bromide [Va; Ar is 4-ClC₆ H₄, R is H] was prepared by hydrogenation of 25.2 g. of 6-(4-chlorophenyl)-3-hexenyl bromide (Preparation C7) according to the procedure described above in Preparation C11, affording 17 g., b.p. 110°-111° C. (0.02 mm.).

C14. 6-(p-Tolyl)hexyl bromide [Va; Ar is 4-CH₃ C₆ H₄, R is H] was prepared by hydrogenation of 6-(p-tolyl)-3-hexenyl bromide according to the procedure described above in Preparation C11.

By replacing the 2-(3,4-methylenedioxyphenyl)ethyl 1-ethylcyclopropyl carbinol in Preparation C1 by a molar equivalent amount of 2-(3,4-methylenedioxyphenyl)ethyl 1-isopropylcyclopropyl carbinol, 2-(3,4-methylenedioxyphenyl)ethyl 1-butylcyclopropyl carbinol, 2-(3,4-dichlorophenyl)ethyl cyclopropyl carbinol, 2-(2,4-dichlorophenyl)ethyl cyclopropyl carbinol, 2-(4-bromophenyl)ethyl cyclopropyl carbonol, 2-(4-fluorophenyl)ethyl cyclopropyl carbinol, 2-(4-benzoyloxyphenyl)ethyl cyclopropyl carbinol, 2-(4-trifluoromethoxyphenyl)ethyl cyclopropyl carbinol or 2-(4-trifluoromethylphenyl)ethyl cyclopropyl carbinol there can be obtained, respectively, 3-isopropyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl bromide [V; Ar is 3,4-methylenedioxyphenyl, R is (CH₃)₂ CH], 3-butyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl bromide [V; Ar is 3,4-methylenedioxyphenyl, R is CH₃ CH₂ CH₂ CH₂ ], 6-(3,4-dichlorophenyl)-3-hexenyl bromide [V; Ar is 3,4-Cl₂ C₆ H₃, R is H], 6-(2,4-dichlorophenyl)-3-hexenyl bromide [V; Ar is 2,4-Cl₂ C₆ H₃, R is H], 6-(4-bromophenyl)-3-hexenyl bromide [V; Ar is 4-BrC₆ H₄, R is H], 6-(4-fluorophenyl)-3-hexenyl bromide [V; Ar is 4-FC₆ H₄, R is H], 6-(4-benzoyloxyphenyl)-3-hexenyl bromide [V; Ar is 4-C₆ H₅ COOC₆ H₄, R is H], 6-4-trifluoromethoxyphenyl)-3-hexenyl bromide [V; Ar is 4-F₃ COC₆ H₄, R is H], or 6-(4-trifluoromethylphenyl)-3-hexenyl bromide [V; Ar is 4-F₃ CC₆ H₄, R is H].

The latter products can be hydrogenated according to the procedure of Preparation C11 to give, respectively, 3-isopropyl-6-(3,4-methylenedioxyphenyl)hexyl bromide [Va; Ar is 3,4-methylenedioxyphenyl, R is (CH₃)₂ CH], 3-butyl-6-(3,4-methylenedioxyphenyl)hexyl bromide [Va; Ar is 3,4-methylenedioxyphenyl, R is CH₃ CH₂ CH₂ CH₂ ], 6-(3,4-dichlorophenyl)hexyl bromide [Va; Ar is 3,4-Cl₂ C₆ H₃, R is H], 6-(2,4-dichlorophenyl)hexyl bromide [Va; Ar is 2,4-Cl₂ C₆ H₃, R is H], 6-(4-bromophenyl)hexyl bromide [Va; Ar is 4-BrC₆ H₄, R is H], 6-(4-fluorophenyl)hexyl bromide [Va; Ar is 4-FC₆ H₄, R is H], 6-(4-trifluoromethoxyphenyl)hexyl bromide [Va; Ar is 4-F₃ COC₆ H₄, R is H], or 6-(4-trifluoromethylphenyl)hexyl bromide [Va; Ar is 4-F₃ CC₆ H₄, R is H].

According to the procedures of Preparations C1-C14 using the appropriate starting materials, the following compounds were prepared.

C15. 6-(2,4-Dichlorophenyl)-3-hexenyl bromide [V; Ar is 2,4-Cl₂ C₆ H₃, R is H], prepared from compound of Preparation B12.

C16. 6-(2,4-Dichlorophenyl)hexyl bromide [Va; Ar is 2,4-Cl₂ C₆ H₃, R is H], prepared by hydrogenation of the compound of Preparation C15.

C17. 6-(4-Acetamidophenyl)-3-hexenyl bromide [V; Ar is 4-CH₃ CONHC₆ H₄, R is H], prepared from the compound of Preparation B13.

C18. 8-(4-Methoxyphenyl)-3,7-octadienyl bromide, BrCH₂ CH₂ CH═CHCH₂ CH₂ CH═CHC₆ H₄ OCH₃ -4, prepared from the compound of Preparation B14.

C19. 6-(4-Dimethylaminophenyl)-3-hexenyl bromide [V; Ar is 4-(CH₃)₂ NC₆ H₄, R is H], prepared from the compound of Preparation B15.

C20. 6-(4-Benzyloxyphenyl)-3-hexenyl bromide [V; Ar is 4-C₆ H₅ CH₂ OC₆ H₄, R is H], prepared from the compound of Preparation B17.

C21. 6-(3,4-Dibenzyloxyphenyl)-3-hexenyl bromide [V; Ar is 3,4-(C₆ H₅ CH₂ O)₂ C₆ H₃, R is H], prepared from the compound of Preparation B18.

C22. 6-(4-Trifluoromethoxyphenyl)-3-hexenyl bromide [V; Ar is 4-F₃ COC₆ H₄, R is H], prepared from the compound of Preparation B19.

C23. 6-(1-Naphthyl)-3-hexenyl bromide [V; Ar is 1-naphthyl, R is H], prepared from the compound of Preparation B20.

C24. 6-(1-Naphthyl)hexyl bromide [Va; Ar is 1-naphthyl, R is H], b.p. 145°-146° C. (0.01 mm.), prepared by hydrogenation of the compound of Preparation C23.

C25. 6-(4-Fluorophenyl)-3-hexenyl bromide [V; Ar is 4-FC₆ H₄, R is H], prepared from the compound of Preparation B21.

C26. 6-(4-Fluorophenyl)hexyl bromide [Va; Ar is 4-FC₆ H₄, R is H], by hydrogenation of the compound of Preparation C25.

C27. 6-(4-Diethylaminophenyl)-3-hexenyl bromide [V; Ar is 4-(C₂ H₅)₂ NC₆ H₄, R is H], prepared from compound of Preparation B22.

C28. 6-(4-Benzyloxy-3,5-dimethoxyphenyl)-3-hexenyl bromide [V; Ar is 3,5-(CH₃ O)₂ -4-C₆ H₅ CH₂ OC₆ H₂, R is H], prepared from compound of Preparation B23.

D. arylalkenyl iodides (VI, IX) and arylalkyl iodides (VIa)

D1. 3-Ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide [VI; Ar is 3,4-methylenedioxyphenyl, R is C₂ H₅ ].

A mixture of 23 g. of 3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl bromide (Preparation C1) and 30 g. of powdered potassium iodide in 250 ml. of dimethylformamide was stirred for about sixteen hours. The reaction mixture was concentrated to remove the solvent and the residue partitioned between cyclohexane and water. The cyclohexane layer was separated; dried over anhydrous magnesium sulfate and evaporated to give 33.0 g. of 3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide as a light yellow oil.

D2. 6-(3,4-Methylenedioxyphenyl)-3-hexenyl iodide [VI; Ar is 3,4-methylenedioxyphenyl, R is H] was prepared from 12.9 g. of 6-(3,4-methylenedioxyphenyl)-3-hexenyl bromide (Preparation C2) and 7 g. of sodium iodide in 120 ml. of acetone, refluxed for three hours, affording 12.5 g. of product as an oil.

D3. 3-Methyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide [VI; Ar is 3,4-methylenedioxyphenyl, R is CH₃ ] was prepared from 19.0 g. of 3-methyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl bromide (Preparation C3) and 10.5 g. of sodium iodide in 125 ml. of acetone, to give 21 g. of product as a yellow oil.

D4. 3-Ethyl-6-(3,4-dimethoxyphenyl)-3-hexenyl iodide [VI; Ar is 3,4-(CH₃ O)₂ C₆ H₃, R is C₂ H₅ ] was prepared from 13.8 g. of 3-ethyl-6-(3,4-dimethoxyphenyl)-3-hexenyl bromide (Preparation C4) and 9 g. of sodium iodide in 120 ml. of acetone, to give 15 g. of product as an oil.

D5. 6-(4-Methoxyphenyl)-3-hexenyl iodide [VI; Ar is 4-CH₃ OC₆ H₄, R is H] was prepared from 24 g. of 6-(4-methoxyphenyl)-3-hexenyl bromide (Preparation C5) and 14.75 g. of sodium iodide in 475 ml. of 2-butanone, to give 28.5 g. of product as an oil.

D6. 6-(4-Methoxyphenyl)hexyl iodide [VIa; Ar is 4-CH₃ OC₆ H₄, R is H] was prepared from 16.3 g. of 6-(4-methoxyphenyl)hexyl bromide (Preparation C11) and 9.93 g. of sodium iodide in 325 ml. of 2-butanone, to give 19.3 g. of product as a pale yellow oil.

D7. 6-Phenylhexyl iodide [VIa; Ar is C₆ H₅, R is H] was prepared from 16 g. of 6-phenylhexyl bromide (Preparation C12) and 10.95 g. of sodium iodide in 325 ml. of 2-butanone, to give 19.1 g. of product as an oil.

D8. 6-(4-Chlorophenyl)hexyl iodide [VIa; Ar is 4-ClC₆ H₄, R is H] was prepared from 17 g. of 6-(4-chlorophenyl)hexyl bromide (Preparation C13) and 10.2 g. of sodium iodide in 325 ml. of acetone, to give 21 g. of product as an oil.

D9. 6-(p-Tolyl)hexyl iodide [VIa; Ar is 4-CH₃ C₆ H₄, R is H] was prepared from 6-(p-tolyl)hexyl bromide (Preparation C14) and sodium iodide in acetone according to the procedure of Preparation D2 above.

D10. 3-Ethyl-6-(4-carbomethoxyphenyl)-3-hexenyl iodide [VI; Ar is 4-CH₃ O₂ CC₆ H₄, R is C₂ H₅ ] was prepared from 17.5 g. of 3-ethyl-6-(4-carbomethoxyphenyl)-3-hexenyl bromide (Preparation C9) and 17.5 g. of sodium iodide in 200 ml. of acetone, to give 14 g. of product as an oil.

D11. 3-Ethyl-6-(3,4-methylenedioxyphenyl)-3,5-hexadienyl iodide [IX; Ar is 3,4-methylenedioxyphenyl, R is C₂ H₅ ] was prepared from 10 g. of 3-ethyl-6-(3,4-methylenedioxyphenyl)-3,5-hexadienyl bromide (Preparation C10) and 6 g. of sodium iodide in 120 ml. of acetone, to give 10.5 g. of product as an oil.

By similar procedures 3-isopropyl-6-(3,4-methylenedioxyphenyl)hexyl bromide, 3-butyl-6-(3,4-methylenedioxyphenyl)hexyl bromide, 6-(3,4-dichlorophenyl)hexyl bromide, 6-(2,4-dichlorophenyl)hexyl bromide, 6-(4-bromophenyl)hexyl bromide, 6-(4-fluorophenyl)hexyl bromide, 6-(4-benzoyloxyphenyl)-3-hexenyl bromide, 6-(4-trifluoromethoxyphenyl)hexyl bromide, or 6-(4-trifluoromethylphenyl)hexyl bromide can be caused to react with sodium iodide to give, respectively, 3-isopropyl-6-(3,4-methylenedioxyphenyl)hexyl iodide [VIa; Ar is 3,4-methylenedioxyphenyl, R is (CH₃)₂ CH], 3-butyl-6-(3,4-methylenedioxyphenyl)hexyl iodide [VIa; Ar is 3,4-methylenedioxyphenyl, R is CH₃ CH₂ CH₂ CH₂ ], 6-(3,4-dichlorophenyl)hexyl iodide [VIa; Ar is 3,4-Cl₂ C₆ H₃, R is H], 6-(2,4-dichlorophenyl)hexyl iodide [VIa; Ar is 2,4-Cl₂ C₆ H₃, R is H], 6-(4-bromophenyl)hexyl iodide [VIa; Ar is 4-BrC₆ H₄, R is H], 6-(4-fluorophenyl)hexyl iodide [VIa; Ar is 4-FC₆ H₄, R is H], 6-(4-benzoyloxyphenyl)-3-hexenyl bromide [VI; Ar is 4-C₆ H₅ COOC₆ H₄, R is H], 6-(4-trifluoromethoxyphenyl)hexyl iodide [VIa; Ar is 4-F₃ COC₆ H₄, R is H], or 6-(4-trifluoromethylphenyl)hexyl iodide [VIa; Ar is 4-F₃ CC₆ H₄, R is H].

According to the procecedures of Preparations D1-D11 using the appropriate starting materials, the following compounds were prepared:

D12. 6-(2,4-Dichlorophenyl)hexyl iodide [VIa; Ar is 2,4-Cl₂ C₆ H₃, R is H], prepared from the compound of Preparation C16.

D13. 6-(4-Acetamidophenyl)-3-hexenyl iodide [VI; Ar is 4-CH₃ CONHC₆ H₄, R is H], prepared from the compound of Preparation C17.

D14. 8-(4-Methoxyphenyl)-3,7-octadienyl iodide, ICH₂ CH₂ CH═CHCH₂ CH₂ CH═CHC₆ H₄ OCH₃ -4, prepared from the compound of Preparation C18.

D15. 6-(4-Dimethylaminophenyl)-3-hexenyl iodide [VI; Ar is 4-(CH₃)₂ NC₆ H₄, R is H], prepared from the compound of Preparation C19.

D16. 6-(4-Benzyloxyphenyl)-3hexenyl iodide [VI; Ar is C₆ H₅ CH₂ OC₆ H₄, R is H], prepared from the compound of Preparation C20.

D17. 6-(3,4-Dibenzyloxyphenyl)-3-hexenyl iodide [VI; Ar is 3,4-(C₆ H₅ CH₂ O)₂ C₆ H₃, R is H], prepared from the compound of Preparation C21.

D18. 6-(4-Trifluoromethoxyphenyl)-3-hexenyl iodide [VI; Ar is 4-F₃ COC₆ H₄, R is H], prepared from the compound of Preparation C22.

D19. 6-(1-Naphthyl)hexyl iodide [VIa; Ar is 1-naphthyl, R is H], prepared from the compound of Preparation C24.

D20. 6-(4-Fluorophenyl)hexyl iodide [VIa; Ar is 4-FC₆ H₄, R is H], prepared from the compound of Preparation C26.

D21. 6-(4-Diethylaminophenyl)-3-hexenyl iodide [VI; Ar is 4-(C₂ H₅)₂ NC₆ H₄, R is H], prepared from the compound of Preparation C27.

D22. 6-(4-Benzyloxy-3,5-dimethoxyphenyl)-3-hexenyl iodide [VI; Ar is 3,5-(CH₃ O)₂ -4-C₆ H₅ CH₂ OC₆ H₂, R is H], prepared from the compound of Preparation C28.

D23. 6-(p-Tolyl)- 3-hexenyl iodide [VI; Ar is 4-CH₃ C₆ H₄, R is H], prepared from the compound of Preparation C8.

EXAMPLE 1

4-[3-Ethyl-6-(3,4-methylenedioxyphenyl)- 3-hexenyl]-3,5-heptanedione [I; Ar is 3,4-methylenedioxyphenyl, R° is H, R' and R" are CH₃ CH₂ CO, Y is C(C₂ H₅)═CHCH₂ CH₂ ].

A solution of 15 g. of the lithium salt of 3,5-heptanedione (prepared as described in Example 8 below) in 100 ml. of tetramethylurea was stirred under nitrogen at room temperature, and 10 g. of 3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide (Preparation D1) was added. The reaction mixture was stirred for forty-eight hours, then concentrated to remove the solvent, and the residue slurried in ether and treated with excess glacial acetic acid. Water was added, the ether layer separated, washed with water and concentrated. The residue was distilled in a molecular still to remove volatile material at 110° C. (0.001 mml.), and the non-volatile residue was chromatographed on 10 g. of activated magnesium silicate in benzene solution and eluted with ethyl acetate to give 4-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione as a yellow oil.

The reaction was repeated starting with 38.4 g. of 3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide and the product was chromatographed twice on activated magnesium silicate. The second chromatogram was eluted with benzene to give 12.4 g. of 4-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione as a yellow oil.

Infrared (IR) (oil film) λ.sub.μ^(max) 2.83 w, 2.95 w; 3.39, 3.92 s (CH); 5.80 s, 5.90 s (C═O); 6.27 ms, 6.23 m, 6.65 s, 6.71 s, 6.94 s (aromatic+CH).

4-[3-Ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione was found to have pesticidal activity when tested against yellow mealworm pupae (tenebrio) at a concentration of 0.1 microgram per insect, against dock beetle larvae at 1 microgram per insect, against yellow fever mosquito lavae at 15 ppm in water and against rhodnius prolixus nymph at 100 micrograms per insect.

EXAMPLE 2

3-[3-Ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-2,4-pentanedione [I; Ar is 3,4-methylenedioxyphenyl, R° is H, R' and R" are CH₃ CO, Y is C(C₂ H₅)═CHCH₂ CH₂ ].

A mixture of 10 g. of the lithium salt of 2,4-pentanedione (prepared by treatment of 2,4-pentanedione in ether with n-butyllithium by the procedure described in Example 8 below) and 10 g. of 3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide (Preparation D1) in 100 ml. of tetramethylurea was heated at 60° C. for forty-eight hours. The reaction mixture was filtered, the filtrate concentrated in vacuo to a volume of about 20 ml., then diluted with 200 ml. of water and extracted with ether. The ether solution was washed with water and saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The dried ether solution was concentrated to remove the solvent, and the residue was chromatographed on silica gel. The chromatograph column was eluted with pentane containing 20% benzene which removed unreacted iodide, and then eluted with benzene containing 20% ether, affording 2.4 g. of 3-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-2,4-pentanedione as an amber oil.

Anal. Calcd. for C₂₀ H₂₇ O₄ : C, 72.48; H, 8.21. Found: C, 72.34; H, 7.93.

IR (oil film)λ.sub.μ^(max) 3.45 mss+shldrs. (CH); 5.80 mss, 5.91 s (C═O); 6.25 m, 6.35 m, 6.67 mss, 6.73 s, 6.96 mss (arom+CH).

Nuclear Magnetic Resonance (NMR) [20% CDCl₃, internal tetramethylsilane (TMS)] δ ppm (Ratio) 6.63(3) (arom); 5.87(2) (O--CH₂ --O); 5.08(1) (═CH); 3.53(1) [(O═C)₂ CH]; 1.5-3.0(16) (aliphatic CH+COCH₃ ×2); 0.9(3) (Me triplet).

3-[3-Ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-2,4-pentanedione was found to be pesticidal against yellow mealworm pupae (tenebrio) at a concentration of 100 micrograms per insect, against dock beetle larvae at 20 micrograms per insect, against cabbage looper larvae at 100 micrograms per insect and against rhodnius prolixus nymph at 30 micrograms per insect.

EXAMPLE 3

3-[3-Ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-2,4-hexanedione [I; Ar is 3,4-methylenedioxyphenyl, R° is H, R' is CH₃ CO, R" is CH₃ CH₂ CO, Y is C(C₂ H₅)═CHCH₂ CH₂ ] was prepared from 23.2 g. of 3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide (Preparation D1) and 22.3 g. of the lithium salt of 2,4-hexanedione (prepared by the procedure described in Example 8 below) in 300 ml. of dimethylformamide according to the procedure described above in Example 2. There was thus obtained 21 g. of crude product which was chromatographed on 600 g. of silica gel in pentane solution containing 20% benzene. The column was eluted with the pentane-benzene-ether solvent series. Benzene containing 3% ether brought out the desired product, 14.5 g. of 3-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-2,4-hexanedione as a yellow oil.

Anal. Calcd. for C₂₁ H₂₈ O₄ : C, 73.24; H, 8.19. Found: C, 73.52; H, 8.32.

IR (oil film) λ₈₂ ^(max) 3.45 mss+shldrs. (CH); 5.83 s, 5.91 s (C═O); 6.33 m, 6.74 s+shldr., 6.96mss (arom and CH). 6.96

NMR (20% CDCl₃, internal TMS) δ ppm (Ratio) 6.70(3) (arom); 5.92(2) (O--CH₂ --0); 5.13(1) (═CH); 3.62(1) [(O═C)₂ CH]; 1.7-2.9(15) (aliph. CH, incl. COCH₃ singlet); 1.03(6) (Me triplet×2).

3-[3-Ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-2,4-hexanedione was found to be pesticidal against yellow mealworm pupae (tenebrio) at a concentration of 10 micrograms per insect, against dock beetle larvae at a concentration of 1 microgram per insect and against rhodnius prolixus nymph at 10 micrograms per insect.

In the silica gel chromatographic procedure of Example 3 it is possible to isolate from the early eluates (pentane containing a minor fraction of benzene) a non-polar substance, which when distilled in vacuo gives 3-ethyl-6-(3,4-methylenedioxyphenyl)-1,3-hexadiene [Xa; R is C₂ H₅ ], b.p. 95°-105° C. (0.055 mm.), n_(D) ²⁵ =1.5440.

Anal. Calcd. for C₁₅ H₁₈ O₂ : C, 78.22; O, 13.89. Found: C, 78.06; O, 13.87.

IR (oil film) λ.sub.μ^(max) 3.45 mss+ shldrs. (CH); 6.10 m, 6.25 mms, 6.67 s, 6.74 s (arom); 6.95 mss (CH).

3-Ethyl-6-[3,4-(methylenedioxy)phenyl]-1,3-hexadiene was found to be pesticidal against dock beetle larvae and rhodnius prolixus nymph.

EXAMPLE 4

Ethyl 2-acetyl-5-ethyl-8-(3,4-methylenedioxyphenyl)-5-octenoate [I; Ar is 3,4-methylenedioxyphenyl, R° is H, R' is CH₃ CO, R" is COOC₂ H₅, Y is C(C₂ H₅)═CHCH₂ CH₂ ] was prepared from 9.6 g. of 3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide (Preparation D1) and 10 g. of the lithium salt of ethyl acetoacetate (prepared by the method described in Example 8 below) in 100 ml. of tetramethylurea according to the procedure described above in Example 2. The reaction was allowed to proceed for five days at 60° C., and the resulting product was isolated and chromatographed on silica gel to give 4.9 g. of ethyl 2-acetyl-5-ethyl-8-(3,4-methylenedioxyphenyl)-5-octenoate as a yellow oil.

Anal. Calcd. for C₂₀ H₂₈ O₅ : C, 69.98; H, 7.83. Found: C, 69.97; H, 7.86.

IR (oil film) λ.sub.λ^(max) 3.45 mss + shldrs. (CH), 5.78 mss, 5.86 s (C═O); 6.15-6.30 m, 6.67 mss, 6.73 s, 6.95 mss (arom and CH).

NMR (20% CDCL₃, internal TMS) δ ppm (Ratio) 6.63(3) (arom); 5.86(2) (--CH₂ --O); 5.10(1) (═CH); 4.17(2) (OCH₂ quartet); 3.33(1) [(O═C)₂ --CH]; 1.7-2.8(13) (aliph. CH incl. COCH₃); 1.25(3), 0.90(3) (Me triplet× 2).

Ethyl 2-acetyl-5-ethyl-8-(3,4-methylenedioxyphenyl)-5-octenoate was found to have a minimum inhibitory concentration in vitro of 6 micrograms per milliliter against equine rhino virus.

EXAMPLE 5

Ethyl 2-propionyl-5-ethyl-8-(3,4-methylenedioxyphenyl)-5-octenoate [I; Ar is 3,4-methylenedioxyphenyl, R° is H, R' is CH₃ CH₂ CO, R" is COOC₂ H₅, Y is C(C₂ H₅)═CHCH₂ CH₂ ] was prepared from 10 g. of 3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide (Peparation D1) and 4.6 g. of the lithium salt of ethyl 3-oxovalerate (prepared by the method described in Example 8 below) in 100 ml. of dimethylformamide by the procedure described above in Example 2. The product was chromatographed on silica gel and eluted with chloroform containing 20% benzene to give 5.5 g. of ethyl 2-propionyl-5-ethyl-8-(3,4-methylenedioxyphenyl)-5-octenoate as an amber liquid.

Anal. Calcd. for C₂₂ H₃₀ O₅ : C, 70.56; H, 8.08. Found: C, 71.70; H, 8.06. C, 71.60; H, 8.09.

Ethyl 2-propionyl-5-ethyl-8-(3,4-methylenedioxyphenyl)-5-octenoate was found to have a minimum inhibitory concentration in vitro of 12 micrograms per millilit r against equine rhino virus.

Ethyl 2-propionyl-5-ethyl-8-(3,4-methylenedioxyphenyl)-5-octenoate was found to be pesticidal against yellow mealworm pupae (tenebrio) at a concentration of 10 micrograms per insect.

EXAMPLE 6

Ethyl 2-butyryl-5-ethyl-8-(3,4-methylenedioxyphenyl)-5-octenoate [I; Ar is 3,4-methylenedioxyphenyl, R° is H, R' is CH₃ CH₂ CH₂ CO, R" is COOC₂ H₅, Y is C(C₂ H₅)═CHCH₂ CH₂ ] was prepared from 20 g. of 3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide (Preparation D1) and 12 g. of lithium salt of ethyl 3-oxohexanoate (prepared by the method described below in Example 8) according to the procedure described above in Example 2. There was thus obtained 11.57 g. of ethyl 2-butyryl-5-ethyl-8-(3,4-methylenedioxyphenyl)-5-octenoate as a light yellow oil.

Anal. Calcd. for C₂₃ H₃₂ O₅ : C, 71.11; H, 8.30. Found: C, 70.89; H, 8.54.

IR (oil film) λ.sub.μ^(max) 3.45 mss+ shldrs. (CH); 5.78 mss, 5.91 s (C═O); 6.24 m, 6.74 mss, 6.68 shldr., 6.96 mss (arom and CH).

NMR (20% CDCl₃, internal TMS) δ ppm (Ratio) 6.73(3) (arom); 5.93(2) (O--CH₂ --O); 5.17(1) (═CH); 4.22(2) (OCH₂ CH₃ quartet); 3.42(1⁺) [(O═C)₂ CH], 0.7-2.8(23) (aliph. CH incl. Me triplet× 3).

Ethyl 2-butyryl-5-ethyl-8-(3,4-methylenedioxyphenyl)-5-octenoate was found to have a minimum inhibitory concentration in vitro of 12 micrograms per milliliter against equine rhino virus.

Ethyl 2-butyryl-5-ethyl-8-(3,4-methylenedioxyphenyl)-5-octenoate was found to be pesticidal against yellow mealworm pupae (tenebrio) at a concentration of 0.3 micrograms per insect and against dock beetle larvae at a concentration of 5 micrograms per insect.

EXAMPLE 7

4-[6-(3,4-Methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione [I; Ar is 3,4-methylenedioxyphenyl, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH═CHCH₂ CH₂ ] was prepared from 12.5 g. of 6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide (Preparation D2) and 12.5 g. of the lithium salt of 3,5-heptanedione in 175 ml. of dimethylformamide. The product was chromatographed on silica gel and eluted with pentane-benzene (1:1) and then with chloroform-benzene (7:3). The latter brought out 7.0 g. of 4-[6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione as a light amber oil.

Anal. Calcd. for C₂₀ H₂₆ O₄ : C, 72.70; H, 7.53. Found: C, 72.48; H, 7.96.

IR (oil film) λ.sub.μ^(max) 3.45 mss+ shldrs. (CH), 5.8 mss, 5.91 s (C═O); 6.25-6.35 m, 6.67 mss, 6.74 s, 6.95 mss (arom and CH). NMR (20% CDCl₃, internal TMS) δ ppm (Ratio) 6.62(3) (arom); 5.85(2) (O--CH₂ --O); 5.35(2) (═CH×2), 3.58(1) [(O═C)₂ CH]; 1.7-2.8(12) (aliph. CH); 1.00(6) (Me triplet× 2).

4-[6-(3,4-Methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione was found to have a minimum inhibitory concentration in vitro of 3-6 micrograms per milliliter against equine rhino virus.

4-[6-(3,4-Methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione was found to be pesticidal against yellow mealworm pupae (tenebrio) at a concentration of 100 micrograms per insect and against dock beetle larvae at 20 micrograms per insect.

EXAMPLE 8

4-[3-Methyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione [I; Ar is 3,4-methylenedioxyphenyl, R° is H, R' and R" are CH₃ CH₂ CO, Y is C(CH₃)═CHCH₂ CH₂ ].

To 40 g. of 3,5-heptanedione in 400 ml. of ether at 0° C. was added dropwise 19.9 g. of n-butyllithium in hexane solution. The mixture was warmed to 25° C., filtered and the solid product washed with ether and dried.

The resulting lithium salt of 3,5-heptanedione (20 g.), 20.6 g. of 3-methyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl iodide (Preparation D3) and 200 ml. of dimethylformamide was stirred at 50° C. for twenty-four hours. Additional dimethylformamide (50 ml.) was then added and the mixture stirred at 60° C. for sixty-five hours. The solution was concentrated in vacuo and the residue triturated with ether several times. The ether solution was washed with water, dried over anhydrous magnesium sulfate and concentrated to give 18 g. of an oil which was chromatographed on 500 g. of silica gel, applied in pentane. The column was eluted with the pentane-benzene-ether solvent sequence. The desired product was brought out by benzene containing 3% ether, affording 10.2 g. of 4-[3-methyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione as a light yellow viscous oil.

Anal. Calcd. for C₂₁ H₂₈ O₄ : C, 73.23; H, 8.19. Found: C, 73.44; H, 8.34.

IR (oil film) λ.sub.μ^(max) 3.45 mss+ shldrs. (CH); 5.82 mss, 5.92 s (C═O); 6.26 m, 6.35 m, 6.68 mss, 6.74 s, 6.96 mss+ shldrs. (arom and CH).

NMR (20% CDCl₃, internal TMS) δ ppm (Ratio) 6.63(3) (arom CH); 5.87(2) (O--CH₂ --O); 5.12(1) (═CH); 3.57(1) [(O═C)₂ CH]; 1.4-2.8(15) (aliph. CH); 1.00(3) (Me triplet× 2).

4-[3-Methyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione was found to have minimum inhibitory concentrations in vitro against rhino-2, equine rhino, para-influenza and resp. syn. virus of 3, 6, 6 and 6 micrograms per milliliter, respectively.

4-[3-Methyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione was found to be pesticidal against yellow mealworm pupae (tenebrio) at a concentration of 3 micrograms per insect, against lock beetle larvae at 5 micrograms per insect and against yellow fever mosquito larvae at 6.6 ppm in water.

In the silica gel chromatographic procedure of Example 8, the early eluates (pentane containing 30 percent benzene) brought out a non-polar fraction which was rechromatographed on 125 g. of silica gel and eluted with pentane and with pentane containing increasing amounts of benzene. Pentane with 4% benzene brought out 3.27 g. of 3-methyl-6-(3,4-methylenedioxyphenyl)-1,3-hexadiene [Xa; R is CH₃ ] as a faintly yellow mobile oil.

Anal. Calcd. for C₁₄ H₁₆ O₂ : C, 77.75; H, 7.46. Found: C, 78.51; H, 7.46.

IR (oil film) λ.sub.μ^(max) 3.45 s+ shldrs. (CH); 6.11 m, 6.24 ms, 6.66 s, 6.74 s (arom); 6.94 s (CH).

3 -Methyl-6-(3,4-methylenedioxyphenyl)-1,3-hexadiene was found to be pesticidal against dock beetle larvae, yellow fever mosquito larvae, rhodnius prolixus nymph and saltmarsh caterpillar eggs.

EXAMPLE 9

4-[3-Ethyl-6-(3,4-methylenedioxyphenyl)hexyl]-3,5-heptanedione [I; Ar is 3,4-methylenedioxyphenyl, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH(C₂ H₅) CH₂ CH₂ CH₂ ].

A mixture of 2.1 g. of 4-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione (Example 1) and 10.2 g. of palladium-on-carbon catalyst in 50 ml. of absolute ethanol was hydrogenated for two and one-half hours. The reaction mixture was filtered and concentrated to remove the solvent. The residue was chromatographed on 75 g. of silica gel in benzene-pentane (1:1). The column was eluted with the pentane-benzene-ether solvent sequence, and benzene containing 1% ether brought out the desired product, affording 2.1 g. of 4-[3-ethyl-6-(3,4-methylenedioxyphenyl)hexyl]-3,5-heptanedione as a colorless oil.

Anal. Calcd. for C.sub. H₃₂ O₄ : 3.44 s+ H, 8.95. 5.80 C, 5.90 ; H, 9.00. 6.24 C, 6.73 ; H, 8.82. 6.94

IR (oil film) λ .sub.μ^(max) 3.44s + shldrs. (CH), 5.8s, 5.90s (C═O), 6.24m, 6.73s, 6.66 shldr., 6.94s, 6.82 shldr. (arom and CH).

NMR (5% CDCl₃, internal TMS) δ ppm (Ratio) 6.3-6.8(3) (arom); 5.86 (2) (O--CH₂ --O); 3.56(1) [(O═C)₂ CH triplet]; 0.7-2.7 (30) CH₂ × 8, Me triplet× 3).

4-[3-Ethyl-6-(3,4-methylenedioxyphenyl)hexyl]-3,5-heptanedione was found to have a minimum inhibitory concentration in vitro against rhino-2, equine rhino, para-influenza and resp. syn. virus of 3 micrograms per milliliter.

4-[3-Ethyl-6-(3,4-methylenedioxyphenyl)hexyl]-3,5-heptanedione was found to be pesticidal against yellow mealworm pupae (tenebrio) at a concentration of 0.3 micrograms per insect.

EXAMPLE 10

4-[(6-(3,4-Methylenedioxyphenyl)hexyl]-3,5-heptanedione [I; Ar is 3,4-methylenedioxyphenyl, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared by hydrogenation of 29 g. of 4-[6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione (Example 7) according to the procedure described above in Examble 9. There was thus obtained 17.2 g. of 4-[6-(3,4-methylenedioxyphenyl)-hexyl]-3,5-heptanedione as a light yellow oil, b.p. 178°-185° C. (0.002 mm.).

Anal. Calcd. for C₂₀ H₂₈ O₄ : C, 72.26; H, 8.49. Found: C, 72.24; H, 8.50.

IR (oil film) λ.sub.μ^(max) 3.45 s, 3.53 shldr., 3.64 shldr. (CH); 5.82 s; 5.92 s (C═O); 6.26 m, 6.35 m (arom ring), 6.67 s, 6.74 s, 6.95 s, 6.87 shldr. (CH).

NMR (20% CDCl₃, internal TMS) δppm (Ratio) 6.63(3) (arom CH); 5.87(2) (O--CH₂ --O); 3.61(1) [(O═C)₂ CH-triplet]; 2.2-2.7(6) (COCH₂ × 2, arom ring-Ch₂); 0.85-2.2(16) (CH, incl. Me triplet× 2).

4-[6-(3,4-Methylenedioxyphenyl)hexyl]-3,5-heptanedione was found to have a minimum inhibitory concentration in vitro of 3 micrograms per milliliter against equine rhino virus.

EXAMPLE 11

4-[6-(3,4-Dimethoxyphenyl)-3-ethyl-3-hexenyl]-3,5-heptanedione [I; Ar is 3,4-(CH₃ O)₂ C₆ H₃, R° is H, R' and R" are CH₃ CH₂ CO, Y is C(C₂ H₅)═CHCH₂ CH₂ ] was prepared from 10 g. of 3-ethyl-6-(3,4-dimethoxyphenyl)-3-hexenyl iodide (Preparation D4) and 10 g. of the lithium salt of 3,5-heptanedione in 120 ml. of dimethylformamide according to the procedure described above in Example 2, affording 6 g. of 4-[6-(3,4-dimethoxyphenyl)-3-ethyl-3-hexenyl]-3,5-heptanedione as an amber oil.

Anal. Calcd. for C₂₃ H₃₄ O₄ : C, 73.76; H, 9.15. Found: C, 73.72; H, 9.06.

4-[6-(3,4-Dimethoxyphenyl)-3-ethyl-3-hexenyl]-3,5-heptanedione was found to be pesticidal against yellow mealworm pupae (tenebrio) at a concentration of 10 micrograms per insect and against dock beetle larvae at a concentration of 20 micrograms per insect.

EXAMPLE 12

4-[6-(4-Methoxyphenyl)-3-hexenyl]-3,5-heptanedione [I; Ar is 4-CH₃ OC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH═CHCH₂ CH₂ ]was prepared from 28.2 g. of 6-(4-methoxyphenyl)-3-hexenyl iodide (Preparation D5) and 19 g. of the lithium salt of 3,5-heptanedione in 250 ml. of dimethylformamide according to the procedure described above in Example 2, affording 19 g. of 4-[6-(4-methoxyphenyl)-3-hexenyl]-3,5-heptanedione as a pale yellow oil, b.p. 162°-167° C. (0.04 mm.).

Anal. Calcd. for C₂₀ H₂₈ O₃ : C, 75.89; H, 8.91. Found: C, 75.92; H, 8.95.

IR (oil film) λ.sub.μ^(max) 3.37-3.53 s (CH); 5.81 s, 5.88 s (C═O); 6.22 m, 6.33 ms. 6.62 s (arom ring); 6.80-6.95 ms (CH).

NMR (20% CDCl₃, internal TMS) δppm (Ratio) 6.67-7.2(4) (arom); 5.35(2) (═CH× 2); 3.73, 3.58(4), [OCH₃, (O═C)₂ --CH triplet]; 1.7-2.9(12) (other aliph. CH); 1.00(6) (Me triplet× 2).

4-[6-(4-Methoxyphenyl)-3-hexenyl]-3,5-heptanedione was found to have a minimum inhibitory concentration in vitro of 3 micrograms per milliliter against equine rhino virus.

EXAMPLE 13

4-[6-(4-Methoxyphenyl)hexyl]-3,5-heptanedione [I; Ar is 4-CH₃ OC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared from 19.1 g. of 6-(4-methoxyphenyl)hexyl iodide (Preparation D6) and 12.8 g. of the lithium salt of 3,5-heptanedione in 175 ml. of dimethylformamide, affording 12.5 g. of 4-[6-(4-methoxyphenyl)hexyl]-3,5-heptanedione as a pale yellow oil, b.p. 162°-163° C. (0.03 mm.).

Anal. Calcd. for C₂₀ H₃₀ O₃ : C, 75.43; H, 9.50. Found: C, 75.67; H, 9.67.

IR (oil film) λ.sub.μ^(max) 3.45 s, 3.53 ms (CH); 5.81 mss, 5.91 s (C═O); 6.23 m, 6.34 m, 6.63 vs (arom ring); 6.8 ms (CH).

NMR (20% CDCl₃, internal TMS) δppm (Ratio) 6.65-7.25(4) (arom); 3.73(3) (OCH₃); 3.62(1) [(O═C)₂ H triplet]; 2.2-2.7(6) (COCH₂ × 2, CH₂ -arom); 2.2-2.7(16) (other aliph. CH incl. Me triplets).

4-[6-(4-Methoxyphenyl)hexyl]-3,5-heptanedione was found to have a minimum inhibitory concentration in vitro of 3 micrograms per milliliter against equine rhino virus.

EXAMPLE 14

4-(6-Phenylhexyl)-3,5-heptanedione [I; Ar is C₆ H₅, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared from 19.1 g. of 6-phenylhexyl iodide (Preparation D7) and 14.1 g. of the lithium salt of 3,5-heptanedione in 195 ml. of dimethylformamide, affording 11.3 g. of 4-(6-phenylhexyl)-3,5-heptanedione as a pale yellow oil, b.p. 135°-136° C. (0.03 mm.).

Anal. Calcd. for C₁₉ H₂₈ O₂ : C, 79.12; H, 9.78. Found: C, 79.49; H, 9.81.

IR (oil film) λ.sub.μ^(max) 3.45 s, 3.34, 3.40, 3.52 shldrs. (CH); 5.81 `mss, 5.91 s (C═O); 6.26 m, 6.33 m, 6.69 m (arom ring); 6.88 ms (CH).

NMR (20% CDCl₃, internal TMS) δppm (Ratio) 7.15(5) (phenyl); 3.60(1) [(O═C)₂ CH triplet]; 2.1-2.8(6) (C═O--CH₂ ×2, arom-CH₂); 1.8-2.1(16) (aliph. CH incl. Me triplet× 2).

4-(6-Phenylhexyl)-3,5-heptanedione was found to have a minimum inhibitory concentration in vitro of 6 micrograms per milliliter against equine rhino virus.

EXAMPLE 15

4-[6-(4-Chlorophenyl)hexyl]-3,5-heptanedione [I; Ar is 4-ClC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared from 21 g. of 6-(4-chlorophenyl)hexyl iodide (Preparation D8) and 13.9 g. of the lithium salt of 3,5-heptanedione in 190 ml. of dimethylformamide, affording 13.5 g. of 4-[6-(4-chlorophenyl)-hexyl]-3,5-heptanedione as a pale yellow oil, b.p. 159°-160° C. (0.03 mm.).

Anal. Calcd. for C₁₉ H₂₇ ClO₂ : C, 70.68; H, 8.43. Found: C, 70.86; H, 8.49.

IR (oil film) λ.sub.μ^(max) 3.44 s, 3.38, 3.52 shldrs. (CH); 5.81 mss, 5.90 s (C═O); 6.38 m, 6.71 s (arom ring); 6.86 ms, 6.93 shldr. (CH).

NMR (20% CDCl₃, internal TMS) δppm (Ratio) 6.8-7.3(4) (arom); 3.62(1) [(O═C)₂ CH triplet]; 2.2-2.7(6) (CO--CH₂ × 2, arom-CH₂); 0.8-2.0(16) (other aliph. CH incl. Me triplet× 2).

4-[6-(4-Chlorophenyl)hexyl]-3,5-heptanedione was found to have a minimum inhibitory concentration in vitro of 1.5 micrograms per milliliter against equine rhino virus.

4-[6-(4-Chlorophenyl)hexyl]-3,5-heptanedione can also be prepared by heating 6-(4-chlorophenyl)hexyl bromide (Preparation C13) with the lithium salt of 3,5-heptanedione in dimethylformamide at 100° C.

EXAMPLE 16

4-[6-(p-Tolyl)hexyl]-3,5-heptanedione [I; Ar is 4-CH₃ C₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared from 6-(p-tolyl)hexyl iodide (Preparation D9) and the lithium salt of 3,5-heptanedione according to the procedure of Example 8, and was obtained in the form of a pale yellow oil, b.p. 145°-146° C. (0.01 mm.).

Anal. Calcd. for C₂₀ H₃₀ O₂ : C, 79.42; H, 10.00. Found: C, 79.58; H, 10.11.

4-[6-(p-Tolyl)hexyl]-3,5-heptanedione was active against equine rhino virus in vitro at 12 micrograms per milliliter.

IR (oil film) λ₈₂ ^(max) 3.43 s, 3.38 shldr., 2.51 mss (CH); 5.81 s, 5.89 s (C═O); 6.33 m, 6.61 ms (arom); 6.86 mss+ shldrs. (CH).

EXAMPLE 17

4-[3-Ethyl-6-(4-carbomethoxyphenyl)-3-hexenyl]-3,5-heptanedione [I; Ar is 4-CH₃ O₂ CC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is C(C₂ H₅)═CHCH₂ CH₂ ] was prepared from 14 g. of 3-ethyl-6-(4-carbomethoxyphenyl)-3-hexenyl iodine (Preparation D10) and 14 g. of the lithium salt of 3,5-heptanedione in 200 ml. of dimethylformamide according to the procedure described above in Example 2. The product was chromatographed on silica gel and eluted with the pentane-benzene-ether solvent series. Benzene containing 2% ether brought out the desired product, 2.6 g. of 4-[3-ethyl-6-(4-carbomethoxyphenyl)-3-hexenyl]-3,5-heptanedione as a yellow oil.

Anal. Calcd. for C₂₅ H₃₂ O₄ : C, 74.16; H, 8.66. Found: C, 74.14; H, 8.53. C, 74.41; H, 8.69.

IR (oil film) λ.sub.μ^(max) 3.44 mss+ shldrs. (CH); 5.77 s, 5.90 shldr. (C═O) 6.24 mms, 6.35 m, 6.63 w; 6.87 mms, 6.98 ms (arom+ CH).

NMR (20% CDCl₃, internal TMS) δ ppm (Ratio) 8.00(2), 7.25(2) (arom); 5.10(1+) (═CH); 3.88(3) (OMe); 3.61(1) [(O═C)₂ CH], 0.7-3.0(22) (aliph. CH incl. Me triplets).

4-[3-Ethyl-6-(4-carbomethoxyphenyl)-3-hexenyl]-3,5-heptanedione was found to have a minimum inhibitory concentration in vitro of 25 micrograms per milliliter against equine rhino virus.

4-[3-Ethyl-6-(4-carbomethoxyphenyl)-3-hexenyl]-3,5-heptanedione was found to be pesticidal against dock beetle larvae at a concentration of 1 microgram per insect.

EXAMPLE 18

4-[3-Ethyl-6-(3,4-methylenedioxyphenyl)-3,5-hexadienyl]-3,5heptanedione [I; Ar is 3.4-methylenedioxyphenyl, R° is H, R' and R" are CH₃ CH₂ CO, Y is C(C₂ H₅)═CHCH═CH] was prepared from 10.5 g. of 3-ethyl-6-(3.4-methylenedioxyphenyl)-3.5-hexadienyl iodide (Preparation D11) and 10 g. of the lithium salt of 3.5-heptanedione in 170 ml. of dimethylformamide. The product was chromatographed on silica gel and the impurities removed by elution with pentane-benzene (1:1). The desired product was brought out by elution with chloroform-benzene (6:4), affording 2 g. of 4-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3,5-hexadienyl]-3,5-heptanedione as an amber oil.

Anal. Calcd. for C₂₂ H₂₈ O₄ : C, 74.13; H, 7.92. Found: C, 74.26; H, 7.91.

4-[3-Ethyl-6-(3.4-methylenedioxyphenyl)-3,5-hexadienyl]-3,5-heptanedione was found to have a minimum inhibitory concentration in vitro of 6 micrograms per milliliter against equine rhino virus.

4-[3-Ethyl-6-(3,4-methylenedioxyphenyl)-3,5-hexadienyl]-3.5-heptanedione was found to be pesticidal against yellow mealworm pupae (tenebrio) at a concentration of 10 micrograms per insect and against dock beetle larvae at a concentration of 20 micrograms per insect.

By procedures similar to those described above 3-isopropyl-6-(3,4-methylenedioxyphenyl)hexyl iodide, 3-butyl-6-(3,4-methylenedioxyphenyl)hexyl iodide, 6-(3,4-dichlorophenyl)hexyl iodide, 6-(2,4-dichlorophenyl)hexyl iodide, 6-(4-bromophenyl)hexyl iodide, 6-(4-fluorophenyl)hexyl iodide, 6-(4-benzoyloxyphenyl)-3-hexenyl iodide, 6-(4-trifluoromethoxyphenyl)hexyl iodide, or 6-(4-trifluoromethylphenyl)hexyl iodide can be caused to react with the lithium salt of 3,5-heptanedione to give, respectively, 4-[3-isopropyl-6-(3,4-methylenedioxyphenyl)hexyl]-3,5-heptanedione [I; Ar is 3,4-methylenedioxyphenyl, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH(C₃ H₇)CH₂ CH₂ CH₂ ], 4-[3-butyl-6-(3,9-methylenedioxyphenyl)hexyl]-3,5-heptanedione [I; Ar is 3,4-methylenedioxphenyl, R° is H, R' and R" are CH₃ CH₂ CO. Y is CH(C₄ H₉)CH₂ CH₂ C₂ ], 4-[6-(3,4-dichlorophenyl)hexyl]-3,5-heptanedione [I; Ar is 3,4-Cl₂ C₆ H₃, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ], 4-[6-(2,4-dichlorophenyl)hexyl]-3,5-heptanedione [I; Ar is 2,4-Cl₂ C₆ H₃, R° is H, R' and R" are CH₃ CH.sub. 2 CO, Y is CH₂ CH₂ CH₂ CH₂ ], 4-[6-(4-bromophenyl)hexyl]-3,5-heptanedione [I; Ar is 4-BrC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ], 4-[6-(4-fluorophenyl)hexyl]-3,5-heptanedione [I; Ar is 4-FC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ], 4[6-(4-benzoyloxyphenyl)-3-hexenyl]-3,5-heptanedione [I; Ar is 4-C₆ H₅ COOC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH═CHCH₂ CH₂ ], 4-[6-(4-trifluoromethoxyphenyl)hexyl]-3,5-heptanedione [I; Ar is 4-F₃ COC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ], or 4-[6-(4-trifluoromethylphenyl)hexyl]-3,5-heptanedione [I; Ar is 4-F₃ CC₆ H₄, R° is H, R° and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ]. 4-[6-(4-Benzoyloxyphenyl)-3-hexenyl]-3,5-heptanedione can be saponified with methanolic potassium carbonate to produce 4-[6-(4-hydroxyphenyl)-3-hexenyl]-3,5-heptanedione [I; Ar is 4-HOC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH═CHCH₂ CH₂ ].

EXAMPLE 19

4-Chloro-4-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione [I; Ar is 3,4-methylenedioxyphenyl, R° is Cl, R' and R" are CH₃ CH₂ CO, Y is C(C₂ H₅)═CHCH₂ CH₂ ].

A solution of 3.1 g. (0.193 mole) of cupric chloride dihydrate and 1.5 g. of lithium chloride in 60 ml. of dimethylformamide was warmed to 90° C. and 6.0 g. (0.0167 mole) of 4-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione (Example 1) was added. The reaction mixture was stirred at 90° C. for two hours, then cooled and concentrated in vacuo to remove the solvent. The residual oil which still contained some starting material was treated again with 2.47 g. of cupric chloride and 1.2 g. of lithium chloride in 40 ml. of dimethylformamide, two hours at 90° C. The product was isolated and chromatographed on 150 g. of silica gel in 50% benzene-pentane. The column was eluted with the same solvent and then with pentane containing increasing proportions of benzene. The desired product was brought out with 65-75% benzene to give 2.95 g. of 4-chloro-4-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione as a light yellow liquid.

Anal. Calcd. for C₂₂ H₂₉ ClO₄ : C, 67.25; H, 7.44; Cl, 9.02. Found: C, 67.38; H, 7.56; Cl, 9.06.

IR (oil film) λ.sub.μ^(max) 3.40, 3.45 mms, 3.49 shldr. (CH); 5.79 mss, 5.88 s (C═O); 6.27 m, 6.67 mss (arom); 6.73 s, 6.95 mss (CH).

NMR (20% CDCl₃, internal TMS) δ PPm (Ratio) 6.63(3) (arom); 5.87(2) (O--CH₂ --O); 5.15(1) (═CH--); 1.67-2.92(14) (CH₂ × 7), 0.7-1.5(9) (Me triplet× 3).

4-Chloro-4-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione was found to have minimum inhibitory concentrations in vitro against rhino-2, para-influenza and resp. syn. virus of 1.25 , 12 and 12 micrograms per milliliter, respectively.

4-Chloro-4-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione was found to be pesticidal against yellow mealworm pupae (tenebrio) at a concentration of 0.3 micrograms per insect and against dock beetle larvae at 5 micrograms per insect.

EXAMPLE 20

4-Methyl-4-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione [I; Ar is 3,4-methylenedioxyphenyl, R° is CH₃ R' and R" are CH₃ CH₂ CO, Y is C(C₂ H₅)═CHCH₂ CH₂ ].

A solution of 6.4 g. (0.042 mole) of 1,5-diazabicyclo-[5.4.0]undec-5-ene and 5.0 g. (0.014 mole) of 4-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione (Example 1) in 50 ml. of absolute ethanol was stirred on an oil bath at 45°-50° C. Methyl iodide (4.0 g., 0.028 mole) in 10 ml. of ethanol was added dropwise over a twenty minute period. During three hours, four additional equivalents of 1,5-diazabicyclo[5.4.0]undec-5-ene and five more equivalents of methyl iodide were added alternately. The mixture was added to 400 ml. of ether, and the ether was extracted with water, dried over anhydrous magnesium sulfate and concentrated. The residue which still contained some starting material was again treated with three equivalents of 1,5-diazabicyclo[5.4.0]undec-5-ene and one equivalent of methyl iodide in ethanol. After the reaction was complete, the product was isolated and chromatographed on silica gel (3.75 g.) using 75% benzene in pentane. The product was eluted with 75% benzene and then with pure benzene; the latter benzene fractions brought out the desired product, affording 1.5 g. of 4-methyl-4-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione as a light yellow oil.

Anal. Calcd. for C₂₃ H₃₂ O₄ : C, 74.16; H, 8.66. Found: C, 74.62; H, 8.71. C, 74.85; H, 8.50.

IR (oil film) λ.sub.μ^(max) 3.39, 3.42 s, 3.48, 3.61 shldrs. (CH); 5.89 s, 5.82 shldr. (C═O); 6.22 m, 6.65 mss, 6.71 s, 6.85 mss, 6.93 s (arom and CH).

NMR (20% CDCl₃, internal TMS) δ ppm (Ratio) 6.75(3) (arom); 5.97(2) (O--CH₂ --O); 5.22(1) (═CH); 1.7-2.9(14) (CH₂ ×7); 2.18(3) (Me singlet); 0.7-1.2(9) (Me triplet× 3).

4-Methyl-4-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione was found to have minimum inhibitory concentrations in vitro against rhino-2, equine rhino, parainfluenza and resp. syn. virus of 0.6, 1.5, 6 and 6 micrograms per milliliter, respectively.

4-Methyl-4-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione was found to be pesticidal against yellow mealworm pupae (tenebrio) at a concentration of 10 micrograms per insect.

By replacing the methyl iodide in the foregoing preparation by isopropyl iodide or n-butyl iodide there can be obtained, respectively, 4-isopropyl-4-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]3,5-heptanedione [I; Ar is 3,4-methylenedioxyphenyl, R° is (CH₃)₂ CH, R' and R" are CH₃ CH₂ CO, Y is C(C₂ H₅)═CHCH₂ CH₂ ], or 4-(n-butyl)-4-[3-ethyl-6-(3,4-methylenedioxyphenyl)-3-hexenyl]-3,5-heptanedione [I; Ar is 3,4-methylenedioxyphenyl, R° is CH₃ CH₂ CH₂ CH₂, R' and R" are CH₃ CH₂ CO, Y is C(C₂ H₅)═CHCH₂ CH₂ ].

According to the procedures described in the foregoing examples, the following compounds were also prepared:

EXAMPLE 21

4[6-(p-Tolyl)-3-hexenyl]-3,5-heptanedione [I; Ar is 4-CH₃ C₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH═CHCH₂ CH₂ ] was prepared from the compound of Preparation D23 and the lithium salt of 3,5-heptanedione, and obtained as a pale yellow oil, b.p. 147°-149° C. (0.02 mm.).

Anal. Calcd. for C₂₀ H₂₈ O₂ : C, 79.95; H, 9.39. Found: C, 80.17; H, 9.43.

IR (oil film) λ.sub.μ^(max) 3.45 mss+shldrs. 3.40, 3.52 (CH); 5.81 s, 5.91 s (C═O); 6.34 m, 6.25 shldr., 6.62 ms (arom); 6.88 ms+shldrs. (CH).

4-[6-(p-Tolyl)-3-hexenyl]-3,5-heptanedione can be hydrogenated catalytically to produce the compound of Example 16.

EXAMPLE 22

4-[6-(2,4-Dichlorophenyl)hexyl]-3,5-heptanedione [I; Ar is 2,4-Cl₂ C₆ H₃, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared from the compound of Preparation D12 and the lithium salt of 3,5-heptanedione, and obtained as a clear orange liquid, b.p. 179°-181° C. (0.3 mm.).

Anal. Calcd. for C₁₉ H₂₆ Cl₂ O₂ : C, 63.87; H, 7.33; Cl, 19.84. Found: C, 64.17; H, 7.42; Cl, 19.83.

IR (oil film) λ.sub.μ^(max) 3.43 mss, 3.38 shldr., 3.51 ms (CH); 5.80 s, 5.89 s (C═O); 6.36 mms, 6.41 m, 6.80 s+shldrs. (arom+CH).

4-[6-(2,4-Dichlorophenyl)hexyl]3,5-heptanedione was active against equine rhino virus in vitro at 3 micrograms per milliliter.

EXAMPLE 23

4-[6-(4-Acetamidophenyl)-3-hexenyl]-3,5-heptanedione [I; Ar is 4-CH₃ CONHC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH═CHCH₂ CH₂ ] was prepared from the compound of Preparation D13 and the lithium salt of 3,5-hetpanedione, and obtained as a viscous amber oil, b.p. 215°-220° C. (0.02 mm.).

Anal. Calcd. for C₂₁ H₂₉ NO₃ : C, 73.44; H, 8.51; N, 4.08. Found: C, 72.95; H, 8.45; N, 4.43.

IR (oil film) λ.sub.μ^(max) 3.12 ms+shldrs. (NH); 3.50 ms+shldrs. (CH); 5.85, 5.97, 6.06 s (C═O, N-C═O); 6.30 s, 6.57 s, 6.65 s, 6.93, 7.00 shldr. (arom+CH).

4-[6-(4-Acetamidophenyl)-3-hexenyl]-3,5-heptanedione was active against equine rhino virus in vitro at 12 micrograms per milliliter.

EXAMPLE 24

4-[8-(4-Methoxyphenyl)-3,7-octadienyl]-3,5-heptanedione [I; Ar is 4-CH₃ OC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH═CHCH₂ CH₂ CH═CH] was prepared from the compound of Preparation D14 and the lithium salt of 3,5-heptanedione, and obtained as a pale yellow oil, b.p. 184°-186° C. (0.03 mm.).

Anal. Calcd. for C₂₂ H₃₀ O₃ : C, 77.15; H, 8.83. Found: C, 76.82; H, 8.84.

IR (oil film) λ.sub.μ^(max) 3.42 mss+shldrs. (CH); 5.78 ms, 5.89 ms (C═O); 6.23 mms, 6.32 m, 6.62 s (arom); 6.85 mms+shldrs. (CH).

4-[8-(4-Methoxyphenyl)-3,7-octadienyl]-3,5-heptanedione was active against equine rhino virus in vitro at 6 micrograms per milliliter. It was also active against para-influenza virus and several strains of human rhino virus at 1.5 micrograms per milliliter.

EXAMPLE 25

4-[8-(4-Methoxyphenyl)octyl]-3,5-heptanedione [I; Ar is 4-CH₃ OC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ CH₂ CH₂ ] was prepared by catalytic hydrogenation (PtO₂) of the compound of Example 24, and obtained as a pale yellow oil, b.p. 176°-177° C. (0.02 mm.).

Anal. Calcd. for C₂₂ H₃₄ O₃ : C, 76.26; H, 9.89. Found: C, 76.05; H, 9.83.

IR (oil film) λ.sub.μ^(max) 3.44 s, 3.51 ms (CH); 5.79 ms, 5.89 s (C═O); 6.21 mms, 6.32 m, 6.61 s (arom); 6.89 ms (CH).

4-[8-(4-Methoxyphenyl)octyl]-3,5-heptanedione was active against equine rhino virus in vitro at 12 micrograms per milliliter.

EXAMPLE 26

4-[6-(4-Dimethylaminophenyl)-3-hexenyl]-3,5-heptanedione [I; Ar is 4-(CH₃)₂ NC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH═CHCH₂ CH₂ ] was prepared from the compound of Preparation D15 and the lithium salt of 3,5-heptanedione, and obtained as a pale yellow oil, b.p. 155°-159° C. (0.003 mm.).

Anal. Calcd. for C₂₁ H₃₁ NO₂ : C, 76.55; H, 9.48; N, 4.25. Found: C, 77.04; H, 9.63; N, 4.61.

IR (oil film) λ.sub.μ^(max) 3.43 s+shldrs. 3.53 ms (CH); 5.79, 5.89 s (C═O); 6.26 ms, 6.32 shldr., 6.39 m, 6.57 s, 6.76 m, 6.90 ms (arom+CH).

4-[6-(4-Dimethylaminophenyl)-3-hexenyl]-3,5-heptanedione was active against equine rhino virus in vitro at 3 micrograms per milliliter. It was also active against para-influenza virus and several strains of human rhino virus at 1.5-7 micrograms per milliliter.

EXAMPLE 27

4-[6-(4-Benzyloxyphenyl)-3-hexenyl]-3,5-heptanedione [I; Ar is 4-C₆ H₅ CH₂ OC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH═CHCH₂ CH₂ ] was prepared from the compound of Preparation D16 and the lithium salt of 3,5-heptanedione, and obtained as a colorless solid, m.p. 36°-37° C. when recrystallized from ether.

Anal. Calcd. for C₂₆ H₃₂ O₃ : C, 79.56; H, 8.22. Found: C, 79.51; H, 8.31.

4-[6-(4-Benzyloxyphenyl)-3-hexenyl]-3,5-heptanedione was active against equine rhino virus in vitro at 3 micrograms per milliliter. It was also active against two strains of human rhino virus at 0.3 micrograms per milliliter.

EXAMPLE 28

4-[6-(4-Hydroxyphenyl)hexyl]-3,5-heptanedione [I; Ar is 4-HOC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared by hydrogenation of 21.4 g. of 4-[6-(4-benzyloxyphenyl)-3-hexenyl]-3,5-heptanedione in the presence of 2.5 g. of 10% palladium-on-carbon catalyst in 200 ml. of absolute ethanol. Hydrogenation was complete in three hours, and the product was isolated and recrystallized from isopropyl alcohol to give 11.5 g. of 4-[6(4-hydroxyphenyl)hexyl]-3,5-heptanedione, m.p. 76°-77° C.

Anal. Calcd. for C₁₉ H₂₈ O₃ : C, 74.96; H, 9.27. Found: C, 74.93; H, 9.30.

In vitro activity of 4-[6-(4-hydroxyphenyl)hexyl]-3,5-heptanedione:

    ______________________________________                                                              Minimum Inhibitory                                                             Concentration                                                                  (micrograms per                                           Challenge virus      milliliter)                                               ______________________________________                                         Herpes simplex type 1 (Sheely strain)                                                               12.0                                                      Herpes simplex type 2 (Curtis strain)                                                               12.0                                                      Herpes simplex type 1 (AMC)                                                                         3.0                                                       Human rhino virus type 2                                                                            3.0                                                       Human rhino virus type 14                                                                           6.0                                                       Human rhino virus type 17                                                                           6.0                                                       Respiratory syncytial virus                                                                         6.0                                                       Parainfluenza type 3 3.0                                                       Equine rhino virus   3.0                                                       ______________________________________                                    

Organ culture and in vivo activity of 4-[6-(4-hydroxyphenyl)hexyl]-3,5-heptanedione:

    ______________________________________                                                               Concn.    % Reduction in                                 Challenge virus                                                                             Tissue   (mcg/ml)  virus yield                                    ______________________________________                                         Influenza A2 Jap 170                                                                        Ferret   100       94                                                          Trachea  200       99.9                                           Equine rhino virus                                                                          Monkey   100       95                                                          Trachea                                                           ______________________________________                                    

4-[6-(4-Hydroxyphenyl)hexyl]-3,5-heptanedione was active at 200 mg/kg when administered intranasally to ferrets infected with influenza A2 Jap 170 or influenza A PR 8.

An ointment containing 2% of 4-[6-(4-hydroxyphenyl)hexyl]-3,5-heptanedione was effective against kerato conjunctivitis caused by herpes simplex type 2 (Curtis strain) in rabbits' eyes. 50% of the animals were protected from keratitis and 83% of the animals failed to develop encephalitis, whereas 83% of the untreated control animals died from encephalitis

The following formulations of 4-[6-(4-hydroxyphenyl)hexyl]-3,5-heptanedione (identified below as "dione") were prepared:

1. Ophthalmic ointments in castor oil base

    ______________________________________                                                         % (weight/weight)                                              ______________________________________                                         Dione             1.00                                                         Neomycin sulfate  0.50                                                         Hydrogenated castor oil                                                                          6.93                                                         Castor oil        91.57                                                                          100.00                                                       ______________________________________                                    

Formulations with 2 and 4% dione was also prepared.

2. Aerosol formulation

    ______________________________________                                                           % (w/w)                                                      ______________________________________                                         Dione                3.8                                                       Dipropylene glycol  15.0                                                       Trichloromonofluoromethane                                                                         48.7                                                       Dichlorodifluoromethane                                                                            32.5                                                                           100.0                                                      ______________________________________                                    

3. Formulation for intranasal administration

    ______________________________________                                                        % (weight per unit volume)                                      ______________________________________                                         Benzalkonium chloride                                                                           0.040                                                         Sodium citrate hydrous                                                                          0.550                                                         Citric acid hydrous                                                                             0.010                                                         Tyloxapol        0.125                                                         Sodium chloride  0.740                                                         Dione            3.10                                                          Purified water q.s. ad                                                                          100                                                           ______________________________________                                    

4. Antiviral cream

    ______________________________________                                                          % (w/w)                                                       ______________________________________                                         Stearic acid       10.0                                                        Cetyl alcohol      1.0                                                         Castor oil         15.0                                                        Sorbitan stearate  2.0                                                         PPG Buteth-660     10.0                                                        Dione              2.0                                                         Polysorbate-60     1.0                                                         Triethanolamine    0.6                                                         Purified water q.s. ad                                                                            100.0                                                       ______________________________________                                    

EXAMPLE 29

4-[6-(3,4-Dihydroxyphenyl)hexyl]-3,5-heptanedione [I; Ar is 3,4-(HO)₂ C₆ H₃, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared from the compound of Preparation D17 and the lithium salt of 3,5-heptanedione, followed by catalytic hydrogenation of the resulting 4-[6-(3,4-dibenzyloxyphenyl)-3-hexenyl]-3,5-heptanedione. It was obtained as an amber oil after chromatography.

Anal. Calcd. for C₁₉ H₂₈ O₄ : C, 71.22; H, 8.81. Found: C, 69.61; H, 8.71.

IR (oil film) λ.sub.μ^(max) 2.96 mss (OH); 3.44 mss, 3.52 ms shldr. (CH); 5.80-5.93 s (C═0); 6.25 ms, 6.60 mss, 6.83-6.95 ms (arom+CH).

4-[6-(3,4-Dihydroxyphenyl)hexyl]-3,5-heptanedione was active against equine rhino virus in vitro at 1.5 micrograms per milliliter. It was also active against para-influenza virus at 6, and against two strains of human rhino virus at 0.3 and 1.5 micrograms per milliliter.

EXAMPLE 30

4-[6-(4-Trifluoromethoxyphenyl)-3-hexenyl]-3,5-heptanedione [I; Ar is 4-F₃ COC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH═CHCH₂ CH₂ ] was prepared from the compound of Preparation D18 and the lithium salt of 3,5-heptanedione, and obtained as a yellow oil, b.p. 138°-140° C. (0.05 mm.).

Anal. Calcd. for C₂₀ H₂₅ F₃ 0₃ : C, 64.85; H, 6.80; F, 15.38. Found: C, 65.03; H, 6.88; F, 15.63.

IR (oil film) λ.sub.μ^(max) 3.43 mss, 3.38 shldr. (CH); 5.79 s, 5.89 s (C═0); 6.31 m, 6.63 mss (arom), 6.87 ms+shldrs. (CH).

4-[6-(4-Trifluoromethoxyphenyl)-3-hexenyl]-3,5-heptanedione was active against equine rhino virus in vitro at 6 micrograms per milliliter.

EXAMPLE 31 4-[6-(4-Trifluoromethoxyphenyl)hexyl]-3,5-heptanedione [I; Ar is 4-F₃ COC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared by catalytic hydrogenation of the compound of Example 30, and obtained as a light yellow oil, b.p. 124°-127° C. (0.001 mm.).

Anal. Calcd. for C₂₀ H₂₇ F₃ O₃ : C, 64.50; H, 7.30; F, 15.30. Found: C, 64.44; H, 7.37; F, 15.22.

IR (oil film) λ.sub.μ^(max) 3.42 s, 3.38 shldr., 3.50 ms (CH); 5.78s, 5.88 s (C═0); 6.30 m, 6.62 mss (arom), 6.84 ms+shldr. (CH).

4-[6-(4-Trifluoromethoxyphenyl)hexyl]-3,5-heptanedione was active against equine rhino virus in vitro at 6 micrograms per milliliter.

EXAMPLE 32

4-[6-(1-Naphthyl)hexyl]-3,5-heptanedione [I; Ar is 1-naphthyl, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared from the compound of Preparation D19 and the lithium salt of 3,5-heptanedione, and obtained as a pale yellow oil, b.p. 185°-187° C. (0.005 mm.).

Anal. Calcd. for C₂₃ H₃₀ O₂ : C, 81.61; H, 8.93. Found: C, 81.55; H, 8.99.

IR (oil film) λ.sub.μ^(max) 3.44 s, 3.30 m, 3.52 ms (CH); 5.81 s, 5.90 s (C═0); 6.29 m, 6.33 shldr., 6.63 m (arom); 6.85+shldr. (CH).

4-[6-(1-Naphthyl)hexyl]-3,5-heptanedione was active against equine rhino virus in vitro at 6micrograms per milliliter.

EXAMPLE 33

4-[6-(4-Fluorophenyl)hexyl]-3,5-heptanedione [I; Ar is 4-FC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared from the compound of Preparation D20 and the lithium salt of 3,5-heptanedione, and obtained as a yellow oil, b.p. 138°-144° C. (0.2 mm.).

Anal. Calcd. for C₁₉ H₂₇ FO₃ : C, 74.48; H, 8.88. Found: C, 74.77; H, 8.90.

IR (oil film) λ.sub.μ^(max) 3.49 s, 3.53 ms+shldrs. (CH); 5.84 mss, 5.94 s (C═0); 6.31, 6.36 m, 6.66 s (arom); 6.88 mms (CH).

EXAMPLE 34

4-[6-(4-Hydroxy-3,5-dimethoxyphenyl)hexyl]-3,5-heptanedione [I; Ar is 3,5-(CH₃ O)₂ -4-HOC₆ H₂, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ], yellow oil, was prepared from the compound of Preparation D22 and the lithium salt of 3,5-heptanedione, followed by catalytic hydrogenation of the resulting 4-[6-(4-benzyloxy-3,5-dimethoxyphenyl)-3-hexenyl]-3,5-heptanedione (light yellow oil).

EXAMPLE 35

(a) 7-(4-Methoxyphenyl)heptyl phenyl sulfide.

Phenyllithium (378 ml., 0.755 mole) was added over a period of 2-5 minutes to a solution of 94.5 g. of thioanisole in 600 ml. of tetrahydrofuran, stirred under nitrogen. The mixture was stirred at room temperature for about 16 hours, then cooled to -70° C. (solid CO₂), and 141 g. of 6-(4-methoxyphenyl)hexyl iodide in 210 ml. of tetrahydrofuran was added slowly. The reaction mixture was stirred at -65° C. for two hours and then allowed to warm to room temperature. Water was added and the mixture extracted with pentane. The pentane extracts were washed with water, dried and concentrated to remove the solvent. The residue was distilled in vacuo, b.p. 171°-174° C. (0.15 mm.). The distillate crystallized and was recrystallized from pentane, to give 7-(4-methoxyphenyl)heptyl phenyl sulfide, m.p. 58°-59° C.

(b) 7-(4-Methoxyphenyl)heptyl iodide.

A mixture of 34 g. of 6-(4-methoxyphenyl)heptyl phenyl sulfide, 156 g. of methyl iodide and 30 g. of sodium iodide in 140 ml. of dimethylformamide was refluxed for 88 hours, additional quantities (50 ml., 70 ml. and 30 ml.) of methyl iodide being added each successive day. The reaction mixture was partitioned between water and pentane, the pentane layer separated and washed with water, dried and concentrated. The residue (46.7 g.) was distilled in vacuo, b.p. 129°-139° C. (0.03 mm.) to give 13.0 g. of 7-(4-methoxyphenyl)heptyl iodide.

(c) 4[7-(4-Methoxyphenyl)heptyl]-3,5-heptanedione [I; Ar is 4-CH₃ OC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ CH₂ ] was prepared from 7-(4-methoxyphenyl)heptyl iodide and the lithium salt of 3,5-heptanedione, and obtained as a pale yellow oil, b.p. 169°-171° C. (0.02 mm.).

Anal. Calcd. for C₂₁ H₃₂ O₃ : C, 75.86; H, 9.70. Found: C, 75.77; H, 9.62.

By replacing the 6-(4-methoxyphenyl)hexyl iodide in part (a) of the foregoing example by a molar equivalent amount of 8-(4-methoxyphenyl)-3,7-octadienyl iodide and performing the transformation of the remainder of the example, there can be obtained 4-[8-(4-methoxyphenyl)-4,8-nonadienyl]-3,5-heptanedione [I; Ar is 4-CH₃ OC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH═CHCH₂ CH₂ CH═CH].

EXAMPLE 36

(a) Diethyl [6-(4-benzyloxyphenyl)-3-hexenyl]malonate.

A mixture of 205.8 g. of 6-(4-benzyloxyphenyl)-3-hexenyl iodide (Preparation D16) and 171 g. of the lithium salt of diethyl malonate in 1650 ml. of dimethylformamide was heated at 50°-60° C. for 16 hours. The reaction mixture was concentrated to dryness, the residue partitioned between water and ether, and the ether layer washed with sodium chloride solution, dried and concentrated to give 226 g. of diethyl [6-(4-benzyloxyphenyl)-3-hexenyl]malonate, used in the next reaction without further purification.

(b) 8-(4-Benzyloxyphenyl)-5-octenoic acid [4-C₆ H₅ CH₂ OC₆ H₄ CH₂ CH₂ CH═CHCH₂ CH₂ CH₂ COOH].

A mixture of 222 g. of diethyl [6-(4-benzyloxyphenyl)-3-hexenyl]malonate, 286 g. of 85% potassium hydroxide and 510 ml. of water was refluxed for two hours. The reaction mixture was cooled, acidified with hydrochloric acid and extracted with chloroform. The chloroform extracts were dried and concentrated, and the residue was dissolved in 600 ml. of xylene and heated at reflux for about 16 hours. The solution was cooled, the solvent removed in vacuo, and the residue crystallized from cyclohexanepentane to give 110 g. of 8-(4-benzyloxyphenyl)-5-octenoic acid, m.p. 63°-65° C.

(c) 8-(4-Benzyloxyphenyl)-5-octenol [4-C₆ H₅ CH₂ OC₆ H₄ CH₂ CH₂ CH═CHCH₂ CH₂ CH₂ CH₂ OH].

A solution of 110 g. of 8-(4-benzyloxyphenyl)-5-octenoic acid in 400 ml. of tetrahydrofuran was added dropwise to a slurry of 13.4 g. of lithium aluminum hydride in 630 ml. of tetrahydrofuran at such a rate as to maintain reflux. The reaction mixture was heated at reflux for four hours, then cooled, and 26.5 ml. of tetrahydrofuran and 26.5 ml. of water were added. The solvents were removed in vacuo and the residue crystallized from cyclohexane to give 98 g. of 8-(4-benzyloxyphenyl)-5-octenol, m.p. 65°-67° C.

(d) 8-(4-Benzyloxyphenyl)-5-octenyl p-toluenesulfonate.

8-(4-Benzyloxyphenyl)-5-octenol (24 g.) was added in portions over a 15 minute period to a solution of 19.5 g. of p-toluenesulfonyl chloride in 600 ml. of dry pyridine at -10° C. The reaction mixture was stirred for one hour at -10° C., then poured into ice-water and stirred for 20 minutes. The mixture was extracted with chloroform, and the latter washed with aqueous hydrochloric acid, aqueous sodium hydroxide, dried and concentrated. The resulting 8-(4-benzyloxyphenyl)-5-octenyl p-toluenesulfonate was used directly in the next reaction without further purification.

(e) 8-(4-Benzyloxyphenyl)-5-octenyl iodide [4-C₆ H₅ CH₂ OC₆ H₄ CH₂ CH₂ CH═CHCH₂ CH₂ CH₂ CH₂ I].

A mixture of 33.2 g. of 8-(4-benzyloxyphenyl)-5-octenyl p-toluenesulfonate, 12.6 g. of sodium iodide and 370 ml. of 2-butanone was heated at reflux for four hours, then filtered and concentrated to remove the solvent. The residue was partitioned between ether and water, and the ether solution was washed with aqueous sodium thiosulfate, dried and concentrated to give 26.4 g. of 8-(4-benzyloxyphenyl)-5-octenyl iodide.

(f) 4-[8-(4-Benzyloxyphenyl)-5-octenyl]-3,5-heptanedione [I; Ar is 4-C₆ H₅ CH₂ OC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH═CHCH₂ CH₂ ] was prepared from 8-(4-benzyloxyphenyl)-5-octenyl iodide and the lithium salt of 3,5-heptanedione, and obtained as an oil used directly in the hydrogenation procedure below.

(g) 4-[8-(4-Hydroxyphenyl)octyl]-3,5-heptanedione [I; Ar is 4-C₆ H₅ CH₂ C₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ CH₂ CH₂ ] was prepared by hydrogenating 4-[8-(4-benzyloxyphenyl)-5-octenyl]-3,5-heptanedione in the presence of palladium-on-carbon catalyst, and obtained as colorless crystals, m.p. 164°-165° C.

Anal. Calcd. for C₂₁ H₃₂ O₃ : C, 75.86; H, 9.70. Found: C, 75.91; H, 9.78.

4-[8-(4-Hydroxyphenyl)octyl]-3,5-heptanedione was active against equine rhino virus in vitro at 3 micrograms per milliliter, and against para-influenza virus at 6 and two strains of human rhino virus at 0.3 and 1.5 micrograms per milliliter.

By replacing 6-(4-benzyloxyphenyl)-3-hexenyl iodide in part (a) of the foregoing example by a molar equivalent amount of 8-(4-methoxyphenyl)-3,7-octadienyl iodide (Preparation D14), and performing the transformations of parts (b)-(f) of said example, there can be obtained 4-[10-(4-methoxyphenyl)-5,9-decadienyl]-3,5-heptanedione [I; Ar is 4-CH₃ OC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH═CHCH₂ CH₂ CH═CH], which can be hydrogenated to afford 4-[10-(4-methoxyphenyl)decyl]-3,5-heptanedione [I; Ar is 4-CH₃ OC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ CH₂ CH₂ CH₂ CH₂ ].

EXAMPLE 37

4-{6-[4-(Methoxybenzoyloxy)phenyl]hexyl}-3,5-heptanedione [I; Ar is 4-CH₃ OC₆ H₄ -COOC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ].

To a solution of 6.8 g. of 4-[6-(4-hydroxyphenyl)- -3,5-heptanedione (Example 28) in 30 ml. of dry pyridine was added 7.65 g. of p-anisoyl chloride over a period of 10 minutes. The reaction mixture was stirred overnight at room temperature and then poured into water. The mixture was extracted with ether, and the ether extracts were washed successively with 2 N hydrochloric acid, water, 5% aqueous sodium bicarbonate, and water, then dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on 270 g. of activated magnesium silicate and eluted with the pentane-benzene-ether solvent series. Benzene-ether 8:2 brought out 4.2 g. of 4-{6-[4-(methoxybenzoyloxy)phenyl]hexyl}-3,5-heptanedione as a light yellow solid.

Anal. Calcd. for C₂₇ H₃₄ O₅ : C, 73.94; H, 7.81. Found: C, 73.53; H, 7.60.

4-{6-[4-(Methoxybenzoyloxy)phenyl]hexyl}-3,5-heptanedione was found to be active in vivo upon intragastral or subcutaneous administration at 200 mg/kg to mice infected with Jap 170 influenza strain, whereby 60% of the medicated mice survived.

EXAMPLE 38

4-{6-[4-(Methylbenzoyloxy)phenyl]hexyl}-3,5-heptanedione [I; Ar is 4-CH₃ C₆ H₄ COOC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared from 4-[6-(4-hydroxyphenyl)hexyl]-3,5-heptanedione and p-toluyl chloride according to the procedure of Example 37, and was obtained in the form of off-white crystals, m.p. 72°-75° C.

Anal. Calcd. for C₂₇ H₃₄ O₄ : C, 76.74; H, 8.11. Found: C, 76.89; H, 8.11.

EXAMPLE 39

4-[6-(4-Hydroxyphenyl)hexyl]-3,5-heptanedione 4-morpholinobutanoate [I; Ar is 4-O(CH₂)₄ N(CH₂)₃ COOC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ].

A suspension of 5 g. of 4-[6-(4-hydroxyphenyl)hexyl]-3,5-heptanedione (Example 28), 3.45 g. of 4-morpholinobutyric acid hydrochloride and 3.74 g. of dicyclohexylcarbodiimide (DDC) in 50 ml. of methylene dichloride was stirred at room temperature for two days. The solid dicyclohexyl urea was removed by filtration and washed with methylene dichloride. The combined washings and filtrate was concentrated to dryness and the residue triturated with ether to induce crystallization of the product. The latter was collected and dried to give 7.45 g. of 4-[6-(4-hydroxyphenyl)hexyl]-3,5-heptanedione 4-morpholinobutanoate in the form of its hydrochloride salt, light tan solid, m.p. 57°-59° C.

Anal. Calcd. for C₂₇ H₄₁ NO₂.HCl: C, 65.37; H, 8.53; N, 2.82; Cl, 7.15. Found: C, 65.11; H, 8.44; N, 3.08; Cl, 7.37.

By replacing the 4-morpholinobutyric acid hydrochloride in the foregoing preparation by a molar equivalent amount of 4-diethylaminobutyric acid hydrochloride there can be prepared 4-[-6-(4-hydroxyphenyl)hexyl]-3,5-heptanedione 4-diethylaminobutanoate [I; Ar is 4-(C₂ H₅)₂ N(CH₂)₃ COOC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ].

The glycinate ester of 4-[6-(4-hydroxyphenyl)hexyl]-3,5-heptanedione [I; Ar is 4-NH₂ CH₂ COOC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] can be prepared by reacting the phenolic compound with carbobenzoxyglycine to form the carbobenzoxyglycine ester, and removing the carbobenzoxy group with acetic acid saturated with hydrogen bromide.

4-[6-(4-Hydroxyphenyl)hexyl]-3,5-heptanedione can be caused to react with acetic anhydride, propionic anhydride, caproyl chloride, succinic anhydride, β-cyclopentylpropionyl chloride, p-nitrobenzoyl chloride, 3,4,5-trimethoxybenzoyl chloride, phenylacetyl chloride or cinnamoyl chloride to give, respectively, the acetate, propionate, caproate, hemisuccinate, β-cyclopentylpropionate, p-nitrobenzoate, 3,4,5-trimethoxybenzoate, phenylacetate or cinnamate ester of 4-[6-(4-hydroxyphenyl)hexyl]-3,5-heptanedione.

EXAMPLE 40

(a) 4-[6-(3-Benzyloxyphenyl)-3-hexenyl]-3,5-heptanedione [I; Ar is 3-C₆ H₅ CH₂ OC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH═CHCH₂ CH₂ ] was prepared according to Reaction Sequence A starting with m-benzyloxybenzaldehyde and cyclopropyl methyl ketone.

(b) 4-[6-(3-Hydroxyphenyl)hexyl]-3,5-heptanedione [I; Ar is 3-HOC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared by catalytic hydrogenation of 4-[6-(3-benzyloxyphenyl)-3-hexenyl]-3,5-heptanedione with palladium-on-carbon. The product was chromatographed on silica gel and eluted with ethyl acetate-chloroform 1:9 to give 4-[6-(3-hydroxyphenyl)-hexyl]-3,5-heptanedione as a colorless oil.

Anal. Calcd. for C₁₉ H₂₈ O₃ : C, 74.96; H, 9.27. Found: C, 74.62; H, 9.34.

EXAMPLE 41

(a) 3-[6-(4-Benzyloxyphenyl)-3-hexenyl]-2,4-pentanedione [I; Ar is 3-C₆ H₅ CH₂ OC₆ H₄, R° is H, R' and R" are CH₃ CO, Y is CH═CHCH₂ CH₂ ] was prepared by reacting 6-(4-benzyloxyphenyl)-3-hexenyl iodide (Preparation D₁₆) with lithium pentane-2,4-dione. The product was chromatographed on activated magnesium silicate and eluted with benzene.

(b) 3-[6-(4-Hydroxyphenyl)hexyl]-2,4-pentanedione ]I; Ar is 3HOC₆ H₄, R° is H, R' and R" are CH₃ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared by catalytic hydrogenation of 3-[6-(4-benzyloxyphenyl)-3-hexenyl ]-2,4-pentanedione and had the m.p. 68°-69° C.

Anal. Calcd. for C₁₇ H₂₄ O₃ : C, 73.88; H, 8.75. Found: C, 74.08; H, 8.80.

EXAMPLE 42

(a) 5-(2-Methoxy-4-chlorobenzoyl)pentyl bromide.

Aluminum chloride (70 g.) was added portionwise to a solution of 110 g. of 6-bromocaproyl chloride in 250 ml. of methylene dichloride. To the resulting solution was added slowly, with cooling and stirring, 72 g. of m-chloroanisole in 250 ml. of methylene dichloride. The reaction mixture was stirred for one hour and poured into 500 ml. of 2N hydrochloric acid and 500 ml. of ice. The organic layer was separated and the aqueous layer extracted with ether. The combined organic layers were washed with sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated. The product containing isomeric mixtures was chromatographed on silica gel and eluted with ethyl acetate-hexane. The first compound eluted (72 g.) was the desired isomer, 5-(2-methoxy-4-chlorobenzoyl)pentyl bromide.

(b) 5-Bromopentyl 2-methoxy-4-chlorophenyl carbinol.

Borane in tetrahydrofuran (240 ml. of 1 M) was added over a period of 15 minutes to a solution of 72 g. of 5-(2-methoxy-4-chlorobenzoyl)pentyl bromide in 240 ml. of tetrahydrofuran. The mixture was stirred 45 minutes in an ice bath, and then 300 ml. of 2 N hydrochloric acid was cautiously added. The mixture was concentrated to a volume of 500 ml., extracted with ether, the ether extracts washed with sodium bicarbonate and dried over anhydrous magnesium sulfate. Evaporation of the solvent afforded 74 g. of oil used in the next reaction without further purification.

(c) 6-(2-Methoxy-4-chlorophenyl)-5-hexenyl iodide.

A mixture of 74 g. of 5-bromopentyl 2-methoxy-4chlorophenyl carbinol, 50 g. of sodium iodide and 500 ml. of 2-butanone was heated under reflux for 2.5 days. The reaction mixture was concentrated, water added and the mixture extracted with ether. The ether extracts were dried over anhydrous magnesium sulfate and concentrated to give 84 g. of oil used directly in the next reaction without further purification.

(d) 4-[6-(2-Methoxy-4-chlorophenyl)-5-hexenyl] -3,5-heptanedione was prepared from 84 g. of 6-(2-methoxy-4-chlorophenyl)-5-hexenyl iodide and lithium 3,5-heptanedione (from 42 g. of 3,5-heptanedione and 2.6 g. of lithium hydride in 400 ml. of dimethylformamide). The product was chromatographed on silica gel and eluted with ethyl acetate-hexane 1:4 to give 56 g. of oil used directly in the next reaction without further purification.

(e) 4-[6-(2-Methoxy-4-chlorophenyl)hexyl]-3,5-heptanedione [I; Ar is 2-MeO-4-ClC₆ H₃, R° is H, R' and R" are CH₃ Ch₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared by hydrogenation of 56 g. of 4-[6-(2-methoxy-4-chlorophenyl)-5-hexenyl]-3,5-heptanedione with 6 g. of 10% palladium-on-carbon catalyst in 340 ml. of benzene. There was thus obtained 56 g. of 4-[6-(2-methoxy-4-chlorophenyl)-hexyl]-3,5-heptanedione in the form of an oil.

(f) 4-[6-(2-Hydroxy-4-chlorophenyl)hexyl]-3,5-heptanedione [I; Ar is 2-HO-4-ClC₆ H₃, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ].

4-[6-(2-Methoxy-4-chlorophenyl)hexyl]-3,5-heptane-dione (1.50 g.) in 10 ml. of methylene dichloride was stirred at -60° to -70° C. (isopropyl alcohol-Dry Ice bath) while 1.5 g. of boron tribromide in 10 ml. of methylene dichloride was slowly added over a period of 15 minutes. The reaction mixture was removed from the cooling bath, stirred for 90 minutes and poured into 100 ml. of water and 50 ml. of ether. The mixture was stirred for 15 minutes and the ether layer separated and washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel and eluted with ethyl acetate-hexane 1:4 to give 1.3 g. of 4-[6-(2-hydroxy-4-chlorophenyl)hexyl] -3,5-heptanedione as an oil. The latter was crystallized from ether-hexane to give a solid with the m.p. 53°-55° C.

(g) 4-[6-(2-Chloro-4-hydroxyphenyl)hexyl]-3,5-heptanedione [I; Ar is 2-Cl-4-HOC₆ H₃, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ].

In part (a) above, the second compound eluted from the chromatogram was the isomeric 5-(2-chloro-4-methoxybenzoyl)pentyl bromide. This was carried through the transformations of parts (b), (c), (d), (e) and (f) above to produce the title compound, m.p. 55°-56° C.

Anal. Calcd. for C₁₉ H₂₇ ClO₃ : C, 67.33; H, 8.03; Cl, 10.46. Found: C, 67.61; H, 7.90; Cl, 10.61.

EXAMPLE 43

(a) p-Anisyl 5-bromopentyl ketone.

Aluminum chloride (400 g.) was added in portions over a period of 2.5 hours to a cooled (10° C.) mixture of 151 g. of 6-bromocaproyl chloride, 78 g. of anisole, 210 ml. of nitrobenzene and 870 ml. of ethylene dichloride. The reaction mixture was stirred for about sixteen hours at room temperature, allowed to stand for another day and then poured into 10 liters of ice-water. The mixture was extracted with ethylene dichloride and the ethylene dichloride extracts concentrated in vacuo. The residue was steam-distilled, and the distill and was extracted with 1.5 liters of benzene. The benzene extracts were washed with water, dried over anhydrous sodium sulfate, decolorized with activated charcoal and concentrated in vacuo. The residue was dissolved in 1.5 liters of benzene, washed with aqueous sodium hydroxide and water, dried over sodium sulfate and concentrated to an orange oil, which crystallized upon stirring with n-hexane to give 161 g. of p-anisyl 5-bromopentyl ketone, m.p. 41°-43° C.

(b) 6-(4-Methoxyphenyl)hexyl bromide.

Zinc (10 mesh, 355 g.) was amalgamated by stirring it in a solution of 35 g. of mercuric chloride in 300 ml. of water and 25 ml. of concentrated hydrochloric acid for 20 minutes. The supernatant was decanted, and to the amalgamated zinc was added 160 g. of p-anisyl 5-bromopentyl ketone, 140 ml. of water, 280 ml. of toluene and 85 ml. of acetic acid. The mixture was warmed to 50° C., and 505 ml. of concentrated hydrochloric acid was added in a thin stream over a 20 minute period. The mixture was heated at reflux for six hours, cooled, and the layers were separated. The organic layer was washed with water, sodium bicarbonate solution and again with water, dried over magnesium sulfate and stripped of solvent in vacuo. The residual yellow oil was distilled to give 97 g. of 6-(4-methoxyphenyl)hexyl bromide, b.p. 134°-139° C. (0.2 mm.).

Alternatively, 6-(4-methoxyphenyl)hexyl bromide was prepared in 95% yield by hydrogenation of p-anisyl 5-bromopentyl ketone in ethanol solution containing 0.8% concentrated hydrochloric acid in the presence of 10% palladium on carbon catalyst.

(c) 6-(4-Hydroxyphenyl)hexyl iodide.

A solution of 68 g. (0.25 mole) of 6-(4-methoxyphenyl)hexyl bromide in 500 ml. of glacial acetic acid was treated with 200 ml. of 50% aqueous hydriodic acid. The reaction was boiled at reflux for 5 hours. During the reflux period the condenser was removed briefly from time to time to allow methyl iodide to escape. The reaction was evaporated to dryness in vacuo. The residue was partitioned between water and ether. The organic phase was washed with water, then with dilute sodium thiosulfate until the iodine color was gone. The clear organic solution was evaporated in vacuo in a warm water bath to give a clear oil, 70 g. (92%) of 6-(4-hydroxyphenyl)hexyl iodide, which crystallized slowly after several days at room temperature.

(d) 4-[6-(4-Hydroxyphenyl)hexyl]-3,5-heptanedione.

Lithium hydride (5.2 g., 0.65 mole) was charged into a 2 liter, 3-necked flask and it was covered with 700 ml. of anhydrous dimethylformamide. After attaching a wet test meter to the system (to check for complete evolution of hydrogen), a solution of 89.0 g. (0.694 mole) of 3,5-heptanedione in 100 ml. of anhydrous dimethylformamide was added slowly over 1 hour. After the completion of the addition, the reaction temperature was 55° C. and 15 liters of hydrogen had been evolved. The mixture was heated on a steam bath for 1 hour and an additional liter of hydrogen was released (Theory - 15.6 liters). The reaction mixture was cooled to 40° C. and 118 g. (0.388 mole) of 6-(4-hydroxyphenyl)hexyl iodide was added and the reaction was stirred at 50° C. for 48 hours.

The mixture was poured into 4 liters of cold water containing 60 ml. of concentrated hydrochloric acid. The product was extracted twice with 800 ml. of ether and the combined extracts were washed with 1 liter of water. The ether solution was dried over anhydrous magnesium sulfate and activated charcoal and evaporated in vacuo. The residue was an amber oil that crystallized on standing. The crude product was treated with 800 ml. of hexane at reflux, the mixture was cooled to -10° C. and filtered. The white solid was washed with cold hexane and then air dried to give 99 g., m.p. 58° C.

This material was dissolved in 150 ml. of warm isopropyl alcohol and the solution was diluted with 750 ml. of pentane. The product was cooled to -10° C., filtered and washed on the funnel with cold hexane and dried at 35° C. in vacuo for 20 hours to yield 55.0 g. (46.6%) of 4-[6-(4-hydroxyphenyl)hexyl]-3,5-heptanedione as a white powder, m.p. 71°-72° C., identical with the compound of Example 28.

EXAMPLE 44

4-[4-(4-Hydroxyphenyl)butyl]-3,5-heptanedione [XIV; n is 4, R' and R" are CH₃ CH₂ CO] was prepared by a procedure closely analogous to that of Example 43. A Friedel-Crafts reaction between anisole and gamma-chlorobutyryl chloride in the presence of aluminum chloride gave p-anisyl-3-chloropropyl ketone. Palladium-on-carbon reduction of the latter afforded 4-(4-methoxyphenyl)butyl chloride, which when treated with potassium iodide in ethyl acetate produced 4-(4-methoxyphenyl)butyl iodide. The iodide was demethylated with boron tribromide to yield 4-(4-hydroxyphenyl)butyl iodide, which was caused to react with the lithium salt of 3,5-heptanedione to give 4-[4-(4-hydroxyphenyl)butyl]-3,5-heptanedione, m.p. 67°-69° C.

4-[4-(4-Hydroxyphenyl)butyl]-3,5-heptanedione was active against herpes virus in vitro at 12 micrograms per milliliter.

EXAMPLE 45

4-[6-(4-Hydroxyphenyl)hexyl]-3,5-heptanedione can also be prepared as follows:

A suspension of 0.5 mole of 6-(4-hydroxyphenyl)hexyl bromide [pepared from 6-(4-methoxyphenyl)hexyl bromide and boron tribromide in methylene dichloride according to the procedure of Example 42f], 0.125 mole of potassium iodide, 1.15 moles of 3,5-heptanedione and 1.05 moles of powdered anhydrous potassium carbonate (dried in vacuo for two hours) in 2 liters of acetone is stirred at reflux for 24 hours. One liter of solvent is distilled off and the remainder of the reaction mixture is poured with stirring into a solution of 4 liters of ice-water containing 160 ml. of concentrated hydrochloric acid. The separated product is extracted with ether and the ether extracts washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The ether is distilled off in vacuo and the excess 3,5-heptanedione removed at 70° C. (0.8 mm.) in a rotary evaporator. The residual product is crystallized from isopropyl alcohol-pentane to give 4-[6-(4-hydroxyphenyl)hexyl]-3,5-heptanedione.

The same reaction can be carried out starting from 6-(4-hydroxyphenyl)hexyl iodide, but omitting the potassium iodide from the reaction mixture.

EXAMPLE 46

4-[6-(2-Methoxyphenyl)hexyl]-3,5-heptanedione [I; Ar is 2-CH₃ OC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared according to the process of Reaction Sequence A via the following intermediates:

2-(2-Methoxyphenyl)vinyl cyclopropyl ketone, b.p. 121°-125° C. (0.5 mm.);

2-(2-Methoxyphenyl)ethyl cyclopropyl carbinol, b.p. 115°-118° C. (0.3 mm.);

6-(2-Methoxyphenyl)-3-hexenyl bromide, b.p. 110°-113° C. (0.1 mm.);

4-[6-(2-Methoxyphenyl)-3-hexenyl]-3,5-heptanedione [I; Ar is 2-CH₃ OC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH═CHCH₂ CH₂ ], b.p. 162°-166° C. (0.05 mm.).

The resulting 4-[6-(2-methoxyphenyl)hexyl]-3,5-heptanedione was obtained in the form of a pale yellow oil.

Anal. Calcd. for C₂₀ H₃₀ O₃ : C, 75.43; H, 9.50. Found: C, 75.84; H, 9.75.

EXAMPLE 47

4-[6-(2-Hydroxyphenyl)hexyl]-3,5-heptanedione [I; Ar is 2-HOC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared by demethylation of 4-[6-(2-methoxyphenyl)hexyl]-3,5-heptanedione (Example 46) with boron tribromide according to the procedure of Example 42f.

Anal. Calcd. for C₁₉ H₂₈ O₃ : C, 74.96; H, 9.27. Found: C, 74.92; H, 9.44.

EXAMPLE 48

3-[6-(3,4-Dihydroxyphenyl)hexyl]-2,4-pentanedione [I; Ar is 3,4-(HO)₂ C₆ H₃, R° is H, R' and R" are CH₃ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared from 6-(3,4-methylenedioxyphenyl)hexyl iodide (prepared by reduction of the compound of Preparation D2) and the lithium salt of 2,4-pentanedione, followed by ether cleavage with boron tribromide. The resulting product was obtained in the form of a light yellow viscous liquid.

Anal. Calcd. for C₁₇ H₂₄ O₄ : C, 69.83; H, 8.27. Found: C, 69.56; H, 8.39.

EXAMPLE 49

4-[6-(4-Hydroxyphenyl)hexyl]-3,5-heptanedione 3,4,5-trimethoxybenzoate [I; Ar is 3,4,5-(CH₃ O)₃ C₆ H₂ COOC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ].

A mixture of 6 g. of 4-]6-(4-hydroxyphenyl)hexyl]-3,5-heptanedione (Example 28) and 55 ml. of pyridine was cooled to 0° C. and 9 g. of 3,4,5-trimethoxybenzoyl chloride was added. The reaction mixture was stirred for 30 minutes at 0° C. and at room temperature overnight. The product was isolated, chromatographed on activated magnesium silicate and eluted with pentane-benzene to give 9 g. of 4-[6-(4-hydroxyphenyl)hexyl]-3,5-heptanedione 3,4,5-trimethoxybenzoate as a yellow viscous oil.

Anal. Calcd. for C₂₉ H₃₈ O₇ : C, 69.85; H, 7.82. Found: C, 69.16; H, 7.70.

EXAMPLE 50

4-[6-(4-Hydroxyphenyl)hexyl]-3,5-heptanedione acetate [I; Ar is 4-(CH₃ COO)C₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared by acetylation of 6-(4-hydroxyphenyl)hexyl iodide with acetic anhydride and reaction of the resulting 6-(4-acetoxyphenyl)hexyl iodide with the lithium salt of 3,5-heptanedione, and was obtained in the form of an amber liquid.

Anal. Calcd. for C₂₁ H₃₀ O₄ : C, 72.79; H, 8.73. Found: C, 72.85; H, 8.81.

EXAMPLE 51

4-[6-(4-Methoxyphenyl)hexyl]-3,5-octanedione [I; Ar is 4-CH₃ OC₆ H₄, R° is H, R' is CH₃ CH₂ CO, R" is CH₃ CH₂ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared from 6-(4-methoxyphenyl)hexyl iodide (Peparation D6) and the lithium salt of 3,5-octanedione, and was obtained as a yellow oil, b.p. 164°-166° C. (0.3 mm.).

Anal. Calcd. for C₂₁ H₃₂ O₃ : C, 75.85; H, 9.70. Found: C, 75.91; H, 9.76.

EXAMPLE 52

3-[6-(4-Methoxyphenyl)hexyl]-2,4-hexanedione [I; Ar is 4-CH₃ OC₆ H₄, R° is H, R' is CH₃ CO, R" is CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] was prepared from 6-(4-methoxyphenyl)hexyl iodide (Preparation D6)and the lithium salt of 2,4-hexanedione, and was obtained as a pale yellow oil after chromatography; copper chelate, m.p. 138°-139° C.

Anal. Calcd. for C₁₉ H₂₈ O₃ : C, 74.96; H, 9.27. Found: C, 74.85; H, 9.30.

EXAMPLE 53

4-[6-(4-Aminosulfonylphenyl)-3-hexenyl]-3,5-heptanedione [I; Ar is 4-H₂ NSO₂ C₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH═CHCH₂ CH₂ ] was prepared according to the reaction sequences described above starting with p-aminosulfonylbenzaldehyde and cyclopropyl methyl ketone, via the following intermediates:

2-(4-Aminosulfonylphenyl)vinyl cyclopropyl ketone, m.p. 173° C.;

2-(4-aminosulfonylphenyl)ethyl cyclopropyl ketone, m.p. 141°-142° C.;

2-(4-aminosulfonylphenyl)ethyl cyclopropyl carbinol, m.p. 92°-95° C.;

4-[6-(4-aminosulfonylphenyl)-3-hexenyl] bromide;

4-[6-(4-Aminosulfonylphenyl)-3-hexenyl] iodide.

4-[6-(4-Aminosulfonylphenyl)-3-hexenyl]-3,5-heptanedione was obtained in the form of a light yellow solid.

Anal. Calcd. for C₁₉ H₂₇ NO₄ S: C, 62.43; H, 7.45; N, 3.83. Found: C, 61.18; H, 7.15; N, 4.02.

EXAMPLE 54

4-[6-(2-Nitrophenyl)hexyl]-3,5-heptanedione [I; Ar is 2-O₂ NC₆ H₄, R° is H, R' and R" are CH₃ CH₂ CO, Y is CH₂ CH₂ CH₂ CH₂ ] can be prepared as follows:

2-Nitrobenzaldehyde is condensed with methyl cyclopropyl ketone to give 2-(2-nitrophenyl)vinyl cyclopropyl ketone. The latter is reduced selectively with hydroxylamine and hydroxylamine O-sulfonic acid in dilute sodium hydroxide solution to yield 2-(2-nitrophenyl)ethyl cyclopropyl ketone, which is then reduced with sodium borohydride to 2-(2-nitrophenyl)ethyl cyclopropyl carbinol. The carbinol is treated in the usual way with phosphorus tribromide and zinc bromide to afford 4-[6-(2-nitrophenyl)-3-hexenyl] bromide. The latter is reacted with potassium iodide, potassium carbonate and 3,5-heptanedione to produce 4-[6-(2-nitrophenyl)-3-hexenyl]-3,5-heptanedione which is selectively reduced with hydroxylamine and hydroxylamine O-sulfonic acid to give the title compound. 

I claim:
 1. A compound of the formula ##STR10## wherein Y is ##STR11## R' is lower-alkanoyl of 2 to 6 carbon atoms; R" is lower-alkanoyl of 2 to 6 carbon atoms;R° is hydrogen; R is hydrogen of lower-alkyl of 1 to 4 carbon atoms; and Ar is phenyl, naphthyl, or phenyl substituted by from one to three monovalent substituents selected from the group consisting of lower-alkyl of 1 to 4 carbon atoms, lower-alkoxy of 1 to 4 carbon atoms, halogen, nitro, trifluoromethyl, trifluoromethoxy and hydroxy.
 2. 4-[6-(3,4-Dimethoxyphenyl)-3-ethyl-3-hexenyl]-3,5-heptanedione, according to claim
 1. 3. 4-[6-(4-Methoxyphenyl)-3-hexenyl]-3,5-heptanedione, according to claim
 1. 4. A compound of the formula ##STR12## wherein Y is ##STR13## R' is lower-alkanoyl of 2 to 6 carbon atoms; R" is lower-alkanoyl of 2 to 6 carbon atoms;R° is hydrogen; R is hydrogen or lower-alkyl of 1 to 4 carbon atoms; and Ar is phenyl, naphthyl or phenyl substituted by from one to three monovalent substituents selected from the group consisting of lower-alkyl of 1 to 4 carbon atoms, lower-alkoxy of 1 to 4 carbon atoms, halogen, nitro, trifluoromethyl, trifluoromethoxy and hydroxy.
 5. 4-[6-(4-Methoxyphenyl)hexyl]-3,5-heptanedione, according to claim
 4. 6. 4-(6-Phenylhexyl)-3,5-heptanedione, according to claim
 4. 7. 4-[6(4-Chlorophenyl)hexyl]-3,5-heptanedione, according to claim
 4. 8. 4-[6-(p-Tolyl)hexyl]-3,5-heptanedione, according to claim
 4. 9. 4-[6-(4-Hydroxyphenyl)hexyl]-3,5-heptanedione, according to claim
 4. 10. 4-[6-(3,4-Dihydroxyphenyl)hexyl]-3,5-heptanedione, according to claim
 4. 11. A compound of the formula ##STR14## wherein n is an integer from 4 to 8, inclusive, and R' and R" are lower-alkanoyl of 2-6 carbon atoms.
 12. 4-[4-(4-Hydroxyphenyl)butyl]-3,5-heptanedione, according to claim
 11. 13. A compound of the formula ##STR15## wherein Y is ##STR16## R' is lower-alkanoyl of 2 to 6 carbon atoms; R" is lower-alkanoyl of 2 to 6 carbon atoms;R° is hydrogen; R is hydrogen or lower-alkyl of 1 to 4 carbon atoms; and Ar is phenyl, naphthyl or phenyl substituted by from one to three monovalent substituents selected from the group consisting of lower-alkyl of 1 to 4 carbon atoms, lower-alkoxy of 1 to 4 carbon atoms, halogen, nitro, trifluoromethyl, trifluoromethoxy and hydroxy.
 14. 4-[8-(4-Methoxyphenyl)-3,7-octadienyl]-3,5-heptanedione, according to claim
 1. 15. A compound of the formula ##STR17## wherein Y is selected from the group consisting of ##STR18## R' is lower-alkanoyl of 2 to 6 carbon atoms; R" is lower-alkanoyl of 2 to 6 carbon atoms;R° is hydrogen; R is hydrogen of lower-alkyl of 1 to 4 carbon atoms; Z is a single bond, vinylene only when the remainder of Y is unsaturated, or ethylene only when Y is saturated; Z' is a single bond, methylene or ethylene; and Ar is hydroxyphenyl.
 16. 4-[8-(4-Hydroxyphenyl)octyl]-3,5-heptanedione, according to claim
 1. 17. A composition for combatting viruses which comprises an antivirally effective amount of at least one compound of the formula ##STR19## wherein Y is selected from the group consisting of ##STR20## R' is lower-alkanoyl of 2 to 6 carbon atoms; R" is lower-alkanoyl of 2 to 6 carbon atoms;R° is hydrogen, lower-alkyl of 1 to 4 carbon atoms or chloro; R is hydrogen or lower-alkyl of 1 to 4 carbon atoms; Z is a single bond, vinylene only when the remainder of Y is unsaturated, or ethylene only when Y is saturated; Z' is a single bond, methylene or ethylene; and Ar is phenyl, naphthyl or phenyl substituted by from one to three monovalent substituents selected from the group consisting of lower-alkyl of 1 to 4 carbon atoms, lower-alkoxy of 1 to 4 carbon atoms, halogen, nitro, trifluoromethyl, trifluoromethoxy and hydroxy;in admixture with a suitable carrier or diluent.
 18. A composition for combatting viruses which comprises an antivirally effective amount of the compound according to claim 9 in admixture with a suitable carrier or diluent.
 19. A method for combatting viruses which comprises contacting a locus of said viruses with a composition containing an antivirally effective amount of at least one compound of the formula ##STR21## wherein Y is selected from the group consisting of ##STR22## R' is lower-alkanoyl of 2 to 6 carbon atoms; R" is lower-alkanoyl of 2 to 6 carbon atoms;R° is hydrogen, lower-alkyl of 1 to 4 carbon atoms or chloro; R is hydrogen or lower-alkyl of 1 to 4 carbon atoms; Z is a single bond, vinylene only when the remainder of Y is unsaturated, or ethylene only when Y is saturated; Z' is a single bond, methylene or ethylene; and Ar is phenyl, naphthyl or phenyl substituted by from one to three monovalent substituents selected from the group consisting of lower-alkyl of 1 to 4 carbon atoms, lower-alkoxy of 1 to 4 carbon atoms, halogen, nitro, trifluoromethyl, trifluoromethoxy and hydroxy;in admixture with a suitable carrier or diluent.
 20. A method for combatting viruses which comprises contacting the locus of said viruses with a composition containing an antivirally effective amount of the compound according to claim 9 in admixture with a suitable carrier or diluent. 